revision #5 - feist-weiller cancer center || …feistweiller.org/clientuploads/clinical...

Distribution Date: December 1, 2011 CTEP Submission Date: November 18, 2011 TO: Phase I: The Phase I portion of this study will be open to the following

Member institutions (not their Affiliates): CITY OF HOPE, UNIVERSITY OF ARIZONA, UNIVERSITY OF ROCHESTER, AND UNIVERSITY OF WASHINGTON; AND to the following CCOP institution: WICHITA CCOP

Phase II: The Phase II portion of this study will be open to ALL SWOG MEMBER, CCOP AND AFFILIATE MEDICAL ONCOLOGISTS effective August 25, 2011.

FROM: Megan M. Wardeski, Protocol Coordinator RE: S0806, "A Phase I/II Trial of Vorinostat (SAHA) (NSC-701852) in

Combination with Rituximab-CHOP in Patients with Newly Diagnosed Advanced Stage Diffuse Large B-Cell Lymphoma (DLBCL)". Study Coordinators: Drs. D.O. Persky, T.P. Miller, and L.M. Rimsza

REVISION #5

Study Coordinator: Daniel O. Persky, M.D. Phone number: 520/626-2218 E-mail: [email protected]

IRB Review Requirements

( ) Full board review required. Reason:

( ) Initial activation (should your institution choose to participate) ( ) Increased risk to patient ( ) Complete study redesign ( ) Addition of tissue banking requirements ( ) Study closure due to new risk information

( √ ) Expedited review allowed

( ) No review required

REVISION #5

Institutions must update their local consent forms to include the changes to the Model Consent Form. SWOG considers that the Model Consent Form changes do not represent an alteration in risk-benefit ratio. Therefore, local accrual does not need to be suspended pending implementation of these changes.

S0806 Revision #5 (contd.)

Patients currently receiving vorinostat, and patients that will be consented prior to local implementation of the consent form changes must be informed of these changes. The manner by which this notification takes place is at the discretion of the local institution. At a minimum, the patient must be notified at the next visit and this notification process must be documented in the patient chart. This revision has been prepared in response to an RA from Dr. Richard Piekarz ([email protected]; 301/496-1196). The protocol referenced above has been revised as follows: 1. Title Page: The version date has been updated. 2. Pages 18-20a, Section 3.6: The CAEPR for vorinostat has been updated from

Version 2.5 (March 24, 2010) to Version 2.6 (October 18, 2011). Page 20a was added to prevent extensive repagination. The following changes have been made to the CAEPR: • The Agent Specific Adverse Event List (ASAEL) is now termed the Specific

Protocol Exceptions to Expedited Reporting (SPEER) and includes grades for adverse events found on the SPEER that are used to determine if expedited reporting is required.

• Added New Risk:

• Also Reported on Vorinostat Trials but with the Relationship to Vorinostat Still Undetermined: Abdominal distension; Acidosis; Agitation; Anal hemorrhage; Atrial flutter; Bloating; Cardiac troponin I increased; Cheilitis; Chest pain - cardiac; Cognitive disturbance; Colitis; Depressed level of consciousness; Depression; Dry skin; Encephalopathy; Esophageal hemorrhage; Facial muscle weakness; Facial nerve disorder; GGT increased; Gastric hemorrhage; General disorders and administration site conditions - Other (angioedema); General disorders and administration site conditions - Other (failure to thrive); Hepatic failure; Hot flashes; Hypoxia; Left ventricular systolic dysfunction; Lethargy; Lipase increased; Lower gastrointestinal hemorrhage; Malaise; Multi-organ failure; Neck pain; Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other (tumor hemorrhage); Nervous system disorders - Other (Guillain-Barre syndrome); Nervous system disorders - Other (head injury); Nervous system disorders - Other (polyneuropathy); Oral hemorrhage; Palmar-plantar erythrodysesthesia syndrome; Paresthesia; Pelvic pain; Pericardial effusion; Personality change; Pharyngeal mucositis; Pleural effusion; Pleuritic pain; Pneumonitis; Psychosis; Seizure; Sinus bradycardia; Sinus tachycardia; Small intestinal obstruction; Stomach pain; Tinnitus; Tumor lysis syndrome; Upper gastrointestinal hemorrhage; Urinary tract pain; Uterine hemorrhage; Vascular access complication; Vascular disorders - Other (arterial thrombosis); Wound dehiscence

• Decrease in Risk Attribution:

• Changed to Less Likely from Likely: Weight loss • Changed to Report But Undetermined from Less Likely: Activated partial

thromboplastin time prolonged; Chills; Thromboembolic event • Provided Further Clarification:

• The following footnote was added to Activated partial thromboplastin time prolonged and INR increased: “Prolongation of prothrombin time and International Normalized Ratio have been observed in patients using vorinostat concomitantly with coumarin-derivative anticoagulants.”

S0806 Revision #5 (contd.)

3. Pages 64-65, Model Consent Form: The following changes have been made to

the vorinostat risks and side-effects section of the Model Consent Form in order to be consistent with the updated CAEPR:

In the Likely Section:

Deleted • Weight loss (moved to Less Likely)

In the Less Likely Section:

Added • Weight loss (moved from Likely) Deleted • Test that shows a problem in blood clotting • Formation of a blood clot that breaks loose and is carried by the blood

stream to plug another blood vessel • Chills

Please append this notice to the front of your copy of the protocol, insert the replacement pages and forward to the responsible Institutional Review Board. This memorandum serves to notify the NCI and SWOG Statistical Center. cc: PROTOCOL & INFORMATION OFFICE

Michael LeBlanc, Ph.D. Bryan Goldman, M.S. Iris Syquia Jeri Jardine Ann Poblenz-Merck

Distribution Date: December 1, 2011 CTEP Submission Date: November 11, 2011 TO: Phase I: The Phase I portion of this study will be open to the following





REVISION #4







REVISION #4

Institutions should update their local consent forms to include the changes to the Model Consent Form. SWOG considers that the Model Consent Form changes do not represent an alteration in risk-benefit ratio. Therefore, local accrual does not need to be suspended pending implementation of these changes.

S0806 Revision #4 (contd.) Page 2

Patients currently on treatment need not be informed of these changes unless required by the local Institutional Review Board (IRB). The protocol referenced above has been revised as follows: 1. Title Page: The version date has been updated. The verbiage in the Phase II

Participants list has been revised as follows: “…after the completion of the Phase I portion,” has been replaced with “…effective August 25, 2011”.

2. Page 42, Sections 12.1-12.5: The following changes have been made:

• Section 12.1: The following language has been added to refer sites to the SWOG Specimen Submission website:

“a. Pathology materials collection and submission instructions can

be accessed on the SWOG Specimen Submission webpage (https://swog.org/Members/ClinicalTrials/Specimens/Lymphpath.asp).”

• Sections 12.2-12.3 and 12.5 have been removed as all of the relevant

information is on the SWOG Specimen Submission webpage. • Section 12.4 has been moved to Section 12.1b.

• Section 12.1c has been added to allow remaining tissue to be banked if

the patient consents. 3. Page 45, Section 14.5: “Dr. Rimsza c/o of the SWOG Lymphoma Repository” has

been revised to “the SWOG Specimen Repository – Solid Tissue, Myeloma and Lymphoma Division”.

4. Page 45, Section 14.6: The reference to Section 15.4a has been replaced with

15.3a in the first bullet. The reference to Section 15.3 has been replaced with 15.2 in the second bullet. The reference to Section 15.4b has been replaced with 15.3b in the third bullet.

5. Pages 47-49, Section 15.2: This section previously contained general specimen

shipping instructions. This has been removed as all relevant information will now be contained on the SWOG Specimen Submission website. Subsequent sections have been renumbered accordingly. Section 15.2 (previously 15.3) has been revised as follows:

• Section 15.2d has been added and reads: “Specimen collection and

submission instructions can be accessed on the SWOG Specimen Submission webpage (http://swog.org/Members/ClinicalTrials/Specimens/LymSpecimens.asp), or via the link on the S0806 protocol abstract page on the SWOG website (www.swog.org).”

• Section 15.2e (previously 15.2c) has been added here. • Section 15.2f (previously 15.2d) has been added here. • Section 15.2g (previously 15.3d) has been added here. • References to Sections 15.2c and 15.2d have been revised to Sections

15.2e and 15.2f, respectively in Section 15.2g. • Section 15.2h has been added and reads: “Specimen collection kits are

not being provided for this submission; sites will use institutional supplies.”


• Section 15.2i has been added and reads “If patient consents to future use of specimens, any remaining blood and serum will be banked at the SWOG Specimen Repository – Solid Tissue, Myeloma and Lymphoma Division, Lab #201”.

6. Page 49, Section 15.3c: This section has been revised with references to

Section 15.2e for shipment guidelines and Section 15.2f for location to ship. 7. Page 49, Section 15.3d: This section was added allowing any remaining tissue

to be banked if the patient consents. 8. Page 72, Model Consent Form: The reference to Section 15.4a has been

replaced with 15.2 in question #2. The reference to Section 15.1 has been replaced with 15.3a in question #3.

9. Page 73, Model Consent Form: The location and contact information for the

SWOG Specimen Repository have been removed from question #5. The reference to Section 15.4b has been updated to 15.3b in question #4.



October 1, 2011 TO: ALL SWOG MEMBER, CCOP AND AFFILIATE MEDICAL ONCOLOGISTS

AND PATHOLOGISTS FROM: SWOG Operations Office RE: IND Safety Report for Suberoylanilide Hydroxamic Acid (SAHA; Vorinostat)

MEMORANDUM IRB Review Requirements ( ) Full board review required. Reason:


( √ ) Expedited review allowed ( ) No review required

MEMORANDUM The following new safety report has been posted regarding an adverse event that occurred in association with the drug SAHA. Please access this safety report via the study’s abstract page or the safety report link on the SWOG website (https://swog.org/safetyreports/safetyreports.asp). This safety report pertains to the following study: S0806 Lymphoma

Report: Sep. 14, 2011 AE #1445639 FU

Protocol amendments are not necessary at this time, but your consent form may be revised to include the information provided in this report if it is deemed necessary by your institution. Please append this notice and this report to your copy of the protocol and forward a copy to your Institutional Review Board (IRB) as required by your local policies and procedures. Should any further information regarding this adverse event be made available, it will be forwarded to you. This memorandum serves to notify the NCI and SWOG Statistical Center. cc: PROTOCOL & INFORMATION OFFICE Michael LeBlanc, Ph.D. Bryan Goldman, M.S. Iris Syquia Jeri Jardine Ann Poblenz – Merck

September 15, 2011 TO: ALL SWOG MEMBER, CCOP AND AFFILIATE MEDICAL ONCOLOGISTS






Report: Aug. 24, 2011 AE #1445639


Distribution Date: September 15, 2011 CTEP Submission Date: August 26, 2011 TO: Phase I: The Phase I portion of this study will be open to the following


Phase II: The Phase II portion of this study will be open to ALL SWOG MEMBER, CCOP AND AFFILIATE MEDICAL ONCOLOGISTS after the completion of the Phase I portion.



REVISION #3







REVISION #3

The protocol referenced above has been revised as follows: 1. Title Page: The version date has been updated. "Southwest Oncology Group"

has been changed to "SWOG" on the participants list and above the title. 2. Page 27, Section 7.4: The "†" footnote has been removed because standard

language has been added to Section 7.6 explaining the use of the Intake Calendar. This change has also been made to Page 30, Section 7.5.

3. Page 30, Section 7.5: The Phase I portion of the study determined that the

Vorinostat dose would be 400 mg on Days 1-9. This information has been added to the table in this section.


4. Page 30, Section 7.6: The following section has been added to the protocol: "Drug compliance will be recorded by patients in the Intake Calendar (see Appendix 19.2). Institutional CRAs will review and ascertain patient adherence with protocol therapy at the end of treatment for each cycle. Calendar should be kept in the patients clinic chart. Note that the Intake Calendar is provided only as a tool for tracking patients compliance. Site may utilize institutional pill diaries or other source documentation in place of the Intake Calendar at the discretion of the treating physician."

5. Page 31, Section 8.3c: The dose modifications for Vorinostat have been added

to the table in this section. 6. Pages 37-38, Section 9.1-9.2: The "¥" footnote has been revised to allow EKG's

to be completed anytime between 28 days prior to registration and Cycle 1 Day 1 treatment. The footnote previously read as follows, "The baseline EKG can be completed anytime between registration and Cycle 1 Day 1 treatment."

7. Page 45, Section 14.8: The phrase "AT THE END OF EACH CYCLE" has been

replaced with "WITHIN 7 DAYS AFTER EACH CYCLE", to provide a specific timeframe for data submission.



September 1, 2011 TO: ALL SWOG MEMBER, CCOP AND AFFILIATE MEDICAL ONCOLOGISTS






Report: Aug. 15, 2011 Mfr Rpt #WAES1101ESP00036


Distribution Date: September 1, 2011 E-mailed Date: August 25, 2011 TO: Phase I: The Phase I portion of this study will be open to the following


Phase II: The Phase II portion of this study will be open to ALL SWOG MEMBER, CCOP AND AFFILIATE MEDICAL ONCOLOGISTS after the completion of the Phase I portion.



MEMORANDUM



( √ ) Full board review required. Reason:

( √ ) Initial activation (should your institution choose to participate, for institutions not previously approved for the Phase I portion)

( ) Increased risk to patient ( ) Complete study redesign ( ) Addition of tissue banking requirements ( ) Study closure due to new risk information

( ) Expedited review allowed

( √ ) No review required (for institution previously participating)

MEMORANDUM, PHASE II ACTIVATION

The Phase I portion of the above-referenced study has been completed. The Phase II portion is now active groupwide. The determined dose for Vorinostat is 400 mg. Please append this notice to the front of your copy of the protocol, insert the replacement pages and forward to the responsible Institutional Review Board. This memorandum serves to notify the NCI and SWOG Statistical Center. cc: PROTOCOL & INFORMATION OFFICE Iris Syquia

Michael LeBlanc, Ph.D. Jeri Jardine Bryan Goldman, M.S. Ann Poblenz-Merck

August 15, 2011 TO: ALL SWOG MEMBER, CCOP AND AFFILIATE MEDICAL ONCOLOGISTS






Report: July 21, 2011 Mfr Rpt #1006USA00950


May 15, 2011 TO: ALL SWOG MEMBER, CCOP AND AFFILIATE MEDICAL ONCOLOGISTS






Report: Apr. 25, 2011 Mfr Rpt #WAES1101ESP00036


Distribution Date: April 1, 2011 CTEP Submission Date: March 23, 2011 TO: Phase I: The Phase I portion of this study will be open to the following


Phase II: The Phase II portion of this study will be open to ALL SOUTHWEST ONCOLOGY GROUP MEMBER, CCOP AND AFFILIATE MEDICAL ONCOLOGISTS after the completion of the Phase I portion.



REVISION #2







REVISION #2

The protocol referenced above has been revised as follows: 1. Title Page: The version date has been updated. 2. Page 22, Section 3.6: The "Drug Returns and Drug Accountability" sections have

been revised to reflect new standard language which replaces the NCI Investigational Agent Accountability Record Form with the Drug Accountability Record Form.

3. Page 24, Section 5.0: The S0806 Prestudy Form number has been changed from

#53189 to #20649. This change has also been made in Section 14.4a (Page 45) and Section 18.2b (Page 58).


4. Page 26, Section 7.1: In the first sentence, "must be obtained" has been changed to "are recommended". The second sentence has been updated to state that "minor deviations from normal limits would be acceptable….". The following sentence has been updated to reflect new standard language for Good Medical Practice, "The Study Coordinator must be contacted if there are significant deviations in the value of theses tests." The sentence now reads as follows, "If there are significant deviations in these tests/assessments that could impact patient safety, it is highly recommended that the registering investigator discuss the patient with the Study Coordinator prior to registering."

5. Page 26, Section 7.1l: The EKG for baseline QT has been removed from this

section because it is not suggested but required per Section 8.6i. 6. Page 28, Section 7.4b.1: "which persists until Day 1 of Cycle 2" has been added

to the definition of non-blood/bone marrow toxicity to clarify the duration. 7. Page 36, Section 8.6i: EKG testing at baseline and Weeks 4 and 16 is required;

therefore, this section has been updated to state that sites must perform the testing. References to Sections 9.1 and 9.2 have been added.

8. Page 36, Section 8.8: This section has been updated to reflect new standard

language for toxicity reporting. "Unexpected or fatal adverse events" has been replaced with "toxicities that meet the expedited reporting criteria". The rest of the sentence has been reworded but content not affected.

9. Pages 37-38, Study Calendars 9.1 and 9.2:

a. EKG's are not necessary at Cycles 4 and 8. Therefore, calendars have been updated, respectively. The pre-study EKG is not required for eligibility but is required for a baseline. Therefore, it has been moved to Cycle 1, Day 1, with "¥" footnote references.

b. The "¥" footnotes have been added to the Study Calendars. They read,

"The baseline EKG can be completed any time between registration and Cycle 1 Day 1 treatment".

c. The "**" footnotes have been revised to indicate that the Good Medical

Practice tests at prestudy are recommended rather than required. 10. Page 50, Section 16.0: This section has been updated to reflect new standard

language for drug accountability. Specific accountability language has been removed and this section now refers sites to the Code of Federal Regulations 21 CFR 312 for procedures and requirements of drug accountability.

11. Page 62, Model Consent Form: EKG's are no longer required at Weeks 10 and

22. Therefore, this statement now reads, "EKG (to check heart function) at Weeks 4 and 16".

Please append this notice to the front of your copy of the protocol, insert the replacement pages and forward to the responsible Institutional Review Board. This memorandum serves to notify the NCI and Southwest Oncology Group Statistical Center. cc: PROTOCOL & INFORMATION OFFICE Iris Syquia

Michael LeBlanc, Ph.D. Jeri Jardine Bryan Goldman, M.S. Ann Poblenz-Merck

January 15, 2011 TO: ALL SWOG, CCOP AND AFFILIATE MEDICAL ONCOLOGISTS AND

PATHOLOGISTS FROM: SWOG Operations Office RE: IND Safety Reports for Suberoylanilide Hydroxamic Acid (SAHA; Vorinostat)




MEMORANDUM The following new safety reports have been posted regarding adverse events that occurred in association with the drug SAHA. Please access these safety reports via the study’s abstract page on the SWOG website (https://swog.org/safetyreports/safetyreports.asp). These safety reports pertain to the following study: S0806 Lymphoma

Reports: Dec. 16, 2010 Mfr Rpt #WAES1011USA03497Jan. 3, 2011 Mfr Rpt #WAES1012USA03694

Protocol amendments are not necessary at this time, but your consent form may be revised to include the information provided in these reports if it is deemed necessary by your institution. Please append this notice and these reports to your copy of the protocol and forward copies to your Institutional Review Board (IRB) as required by your local policies and procedures. Should any further information regarding these adverse events be made available, it will be forwarded to you. This memorandum serves to notify the NCI and SWOG Statistical Center. cc: PROTOCOL & INFORMATION OFFICE Michael LeBlanc, Ph.D. Bryan Goldman, M.S. Iris Buchanan Jeri Jardine Scott Kurruk Ann Poblenz – Merck

Distribution Date: January 15, 2011 E-mail Date: January 3, 2011 CTEP Submission Date: December 23, 2010 TO: Phase I: The Phase I portion of this study will be open to the following



FROM: Megan Wardeski, Protocol Coordinator RE: S0806, "A Phase I/II Trial of Vorinostat (SAHA) (NSC-701852) in


REVISION #1







REVISION #1

The protocol referenced above has been revised as follows: 1. Title Page: The version date has been updated. Wichita CCOP has been added

to the list of Phase I participants. 2. Page 27, Section 7.4: The "*" footnote has been added recommending growth-

factors after vorinostat dosing is complete. 3. Page 28, Section 7.4a: The dosing levels have been relabeled from "1,2,3" to "0,

-1, -2" to indicate dose de-escalation.


4. Page 29, Section 7.4d: This section has been updated to be consistent with

Section 7.4a. 5. Page 29, Section 7.4d: The second sentence has been revised to clarify what it

means for a toxicity to resolve. It now reads, "A patient on the Phase I portion of the study who develops a DLT while on Level -1 should have treatment held until the toxicity resolves (generally to Grades 0-1 except as noted in Sections 7.4b and 8.0), and then may continue on treatment at Dose Level -2.

6. Page 37, Section 9.1: The "†" footnote has been updated to be consistent with

Section 7.4a. 7. Page 45, Section 14.4c: The Lymphoma Baseline Tumor Assessment Form

number has been updated from #39601 to #48031. 8. Page 46, Section 14.10c: The Lymphoma Follow-Up Tumor Assessment Form

number has been updated from #27780 to #64395. 9. Page 46, Section 14.11: The Lymphoma Follow-Up Tumor Assessment Form

number has been updated from #27780 to #64395. 10. Page 51, Section 16.1b: All paper AdEERs forms have been removed from the

CTEP website. This section has been updated accordingly. 11. Page 58, Section 18.2g: The Lymphoma Baseline Tumor Assessment Form

(Form #39601) has been updated to Form #48031. 12. Page 58, Section 18.2h: The Lymphoma Follow-Up Tumor Assessment Form

number has been updated from #27780 to #64395. 13. Page 73, Consent Form: The following statement has been added: "The cost of

the Day 9 biopsy procedure will be covered up to a defined amount". Institutions should update their local consent forms to include the changes to the Model Consent Form. The SWOG considers that the Model Consent Form changes do not represent an alteration in risk-benefit ratio. Therefore, local accrual does not need to be suspended pending implementation of these changes. Patients currently on treatment need not be informed of these changes unless required by the local Institutional Review Board (IRB).

14. Master Forms Set: The S0806 Registration Worksheet (Form #38032) has been

updated to be consistent with the consent form. The version date and form number have not changed.

15. Master Forms Set: The S0806 Dose-Limiting Toxicity Rapid Reporting Form has

been updated with online submittal instructions. The version date and form number have not changed.

16. Master Forms Set: The Lymphoma Baseline Tumor Assessment Form (Form

#39601) has been replaced with the Lymphoma Baseline Tumor Assessment Form (Form #48031).

17. Master Forms Set: The Lymphoma Follow-Up Tumor Assessment Form (Form

#27780) has been replaced with the Lymphoma Follow-Up Tumor Assessment Form (Form #64395).


Please append this notice to the front of your copy of the protocol, insert the replacement pages and forward to the responsible Institutional Review Board. This memorandum serves to notify the NCI and Southwest Oncology Group Statistical Center. cc: PROTOCOL & INFORMATION OFFICE

Michael LeBlanc, Ph.D. Bryan Goldman, M.S. Iris Buchanan Jeri Jardine Scot Kurruk Ann Poblenz-Merck

December 15, 2010 TO: ALL SOUTHWEST ONCOLOGY GROUP, CCOP AND CGOP MEDICAL

ONCOLOGISTS AND PATHOLOGISTS FROM: SWOG Operations Office RE: Myeloma/Lymphoma Repository Closure


( ) Full board review required. Reason: ( ) Initial activation (should your institution choose to participate) ( ) Increased risk to patient ( ) Complete study redesign ( ) Addition of tissue banking requirements ( ) Study closure due to new risk information


( √ ) No review required

MEMORANDUM

The purpose of this memorandum is to inform sites of the holiday closure schedule for the Myeloma/Lymphoma Repository. The repository will be closed from December 24, 2010 through January 2, 2011, and will not be accepting shipments between those dates. Please plan your specimen shipments accordingly. This upcoming holiday closure schedule pertains to the following studies: SWOG-8819 Lymphoma S0777 Myeloma SWOG-8947 Lymphoma S0801 Lymphoma SWOG-9245 Lymphoma S0806 Lymphoma S0120 Myeloma S0816 Lymphoma Please append this notice to the front of your copy of the protocol. This memorandum serves to notify the NCI and the SWOG Statistical Center. cc: PROTOCOL & INFORMATION OFFICE Tracy Maher

John Crowley, Ph.D. Karin Rantala Antje Hoering, Ph.D. Monica Toth Michael LeBlanc, Ph.D. Michael Kelly – CALGB Bryan Goldman, M.S. Ryan Palmer – ECOG Rachael Sexton, M.S. Maddy Balois Oullette – CTSU Joseph Unger, M.S. Kathleen DeRose – GlaxoSmithKline Iris Buchanan Millennium – CTEP Updates Desk Jeri Jardine Tom Street – Celgene Laura Kingsbury Laura Cannon – AG Mednet

November 15, 2010 TO: Phase I: The Phase I portion of this study will be open to the following

Member institutions (not their Affiliates): CITY OF HOPE, UNIVERSITY OF ARIZONA, UNIVERSITY OF ROCHESTER, AND UNIVERSITY OF WASHINGTON


FROM: Megan Wardeski, Protocol Coordinator RE: S0806, "A Phase I/II Trial of Vorinostat (SAHA) (NSC-701852) in


STATUS NOTICE



( √ ) Full board review required. Reason:

( √ ) Initial activation (should your institution choose to participate) ( ) Increased risk to patient ( ) Complete study redesign ( ) Addition of tissue banking requirements ( ) Study closure due to new risk information



ACTIVATION

The Phase I portion of the study referenced above is now open for participation. Note that this portion of the study is available only to the institutions listed on the title page. This memorandum serves to notify the NCI and Southwest Oncology Group Statistical Center. cc: PROTOCOL & INFORMATION OFFICE

Michael LeBlanc, Ph.D. Bryan Goldman, M.S. Iris Buchanan Jeri Jardine Scot Kurruk

PRIVILEGED COMMUNICATION Revised 8/26/11 S0806 FOR INVESTIGATIONAL USE ONLY Activated: November 15, 2010 Revised 12/23/10 Revised 11/11/11

SWOG

A PHASE I/II TRIAL OF VORINOSTAT (SAHA) (NSC-701852) IN COMBINATION WITH RITUXIMAB-CHOP IN PATIENTS WITH NEWLY DIAGNOSED ADVANCED STAGE DIFFUSE LARGE B-CELL

LYMPHOMA (DLBCL) Page 1.0 OBJECTIVES....................................................................................................................3 2.0 BACKGROUND ................................................................................................................3 3.0 DRUG INFORMATION .....................................................................................................6 4.0 STAGING CRITERIA ......................................................................................................22 5.0 ELIGIBILITY CRITERIA ..................................................................................................24 6.0 STRATIFICATION FACTORS ........................................................................................26 7.0 TREATMENT PLAN........................................................................................................26 8.0 TOXICITIES TO BE MONITORED AND DOSAGE MODIFICATIONS ..........................31 9.0 STUDY CALENDAR .......................................................................................................37 10.0 CRITERIA FOR EVALUATION AND ENDPOINT DEFINITIONS...................................39 11.0 STATISTICAL CONSIDERATIONS................................................................................41 12.0 DISCIPLINE REVIEW.....................................................................................................41 13.0 REGISTRATION GUIDELINES ......................................................................................42 14.0 DATA SUBMISSION SCHEDULE ..................................................................................44 15.0 SPECIAL INSTRUCTIONS.............................................................................................46 16.0 ETHICAL AND REGULATORY CONSIDERATIONS.....................................................49 17.0 BIBLIOGRAPHY .............................................................................................................55 18.0 MASTER FORMS SET ...................................................................................................57 19.0 APPENDIX ......................................................................................................................96

PARTICIPANTS: Phase I: The Phase I portion of this study will be open to the following Member

institutions (not their Affiliates): CITY OF HOPE, UNIVERSITY OF ARIZONA, UNIVERSITY OF ROCHESTER, AND UNIVERSITY OF WASHINGTON; AND to the following CCOP institution: WICHITA CCOP.


STUDY COORDINATORS: AGENTS: Primary Study Coordinator: Cyclophosphamide (Cytoxan®) (NSC-26271) Daniel O. Persky, M.D. (Medical Oncology) Doxorubicin (Adriamycin) (NSC-123127) Arizona Cancer Center Prednisone (NSC-10023) 1515 N. Campbell Avenue, Room 1969J Rituximab Chimeric Monoclonal anti-CD20 Tuscon, AZ 85724-5024 Antibody (IDEC-C2B8) (NSC-687451) Phone: 520/626-2218 Vincristine (Oncovin) (NSC-67574) FAX: 520/626-2225 NCI Supplied Agent: E-mail: [email protected] Vorinostat (Suberoylanilide Hydroxamic Acid; SAHA) Paging Service: 520/694-5868 (NSC-701852) (IND-71976) BIOSTATISTICIANS: Co Study Coordinator: Thomas P. Miller, M.D. (Medical Oncology) Bryan Goldman, M.S. (Biostatistics) Arizona Cancer Center Michael LeBlanc, Ph.D. (Biostatistics) 1515 N. Campbell Avenue, Room 1969C Southwest Oncology Group Statistical Center Tuscon, AZ 85724-5024 at Fred Hutchinson Cancer Research Center Phone: 520/626-8908 1100 Fairview Avenue North, M3-C102 FAX: 520/626-2225 P.O. Box 19024 E-mail: [email protected] Seattle, WA 98109-1024 Phone: 206/667-4623 FAX: 206/667-4408 Email: [email protected] (Version Date: 11/18/11) Email: [email protected] mb

S0806 Page 2

STUDY COORDINATORS (contd.): Lisa M. Rimsza, M.D. (Pathology/Translational Medicine) Arizona Cancer Center 1501 N. Campbell Avenue, Room 5211 Tucson, AZ 85724 Phone: 520/626-8396 FAX: 520/626-5243 E-mail: [email protected]

S0806 Page 3

1.0 OBJECTIVES This study will be conducted in two phases: Phase I: 1.1 To find a safe dose of vorinostat to be used in combination with R-CHOP (vorinostat-R-

CHOP). Phase II: 1.2 To estimate the 2-year progression-free survival rate in patients with newly diagnosed

diffuse large B-cell lymphoma (DLBCL) treated with vorinostat and R-CHOP therapy (vorinostat-R-CHOP).

1.3 To estimate the response rate (complete and partial) and 2-year overall survival rate. 1.4 To evaluate the toxicity of vorinostat-R-CHOP in patients with newly diagnosed DLBCL. 1.5 To assess whether pre-treatment acetylation status of histones, expression of MHC

Class II genes, and/or percentage of CD8+ tumor infiltrating lymphocytes (TIL) correlate with progression-free survival.

1.6 To explore whether treatment with vorinostat-R-CHOP increases histone acetylation,

alters expression of MHC class II proteins, or alters percentage of T-cell subsets (CD8+, CD4+, FOXP3+) or infiltrating macrophages.

1.7 To explore whether histone acetylation status of tumor tissues correlates with MHC class

II expression of peripheral blood B cells and lymphocyte subsets. 1.8 To explore whether the change in systemic levels of immune cytokines with vorinostat-R-

CHOP correlates with lymphoma symptoms, response, progression-free or overall survival.

2.0 BACKGROUND Loss of major histocompatibility Class II antigens (MHC Class II) in diffuse large B-cell lymphomas (DLBCL) is associated with a decreased CD8+ tumor-infiltrating T-lymphocyte response and poor patient survival, independent of international prognostic index (IPI) score or histologic subtype. (1) Further investigations indicate that deletion of the MHC Class II genes is infrequent in MHC II negative cases and that altered transcription of the MHC Class II gene complex is likely under the control of the master transactivator, CIITA. (2) Regulation of CIITA and its effects on MHC Class II expression is therefore a potential therapeutic strategy in DLBCL. Epigenetic mechanisms such as hypermethylation of DNA or deacetylation of histones are normal physiologic mechanisms for silencing gene expression in order to regulate numerous cellular activities. CIITA is both itself regulated by histone acetylation and, in turn, modifies H3 and H4 histone acetylation at the HLA-DRA promoter region in human B cell lines. (3,4) Importantly, both H3 and H4 acetylation are inhibited by vorinostat (SAHA), a histone deacetylase inhibitor (HDACI) that is the proposed drug for use in this study. (5) The hypothesis is that the combination of vorinostat with standard chemotherapy will enhance MHC class II expression and improve patient outcome in DLBCL, possibly through improving CD8+ T cell infiltration and immunosurveillance. In the trial S0520, at least one patient treated with an HDACI has shown increased levels of MHC Class II and increased numbers of CD8+ T cells (unpublished data). Histone deacetylase inhibitors have been shown to affect other aspects of the immune system. In mice and primates, HDACI increased Foxp3 gene expression and T regulatory (Treg) cell numbers, particularly through HDAC9. (6,7) Dysregulation, primarily decreases, in pro-inflammatory cytokines were also reported in rodents. (8) In humans, increased numbers of T regulatory cells were found in NHL patients in both their peripheral blood and lymphoma tissue

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samples, raising the question of whether Treg cells are responsible for the disordered immune function in lymphomas. The effects of HDACI in patients with lymphoma, particularly the different T cell subsets in addition to CD8+ cells, may be of clinical relevance. Furthermore, even low doses of vorinostat were recently shown to dramatically decrease pro-inflammatory cytokines such as IL-2, IFN-gamma, TNF-alpha, and IL-6. (9) This suppression of cytokines may be of importance to the clinical effect of histone deacetylase inhibition on symptoms such as pruritus or systemic (“B”) symptoms of lymphoma, as well as potentially affecting lymphoma growth through changes in the microenvironment. HDACI have also been shown to directly induce the differentiation, growth arrest and apoptosis of multiple hematological malignant cell lines, both by the induction as well as the repression of critical genes that regulate tumor cell growth and differentiation. Vorinostat is an HDACI with an extensive record of efficacy. It is the first drug of its class that was approved by the U.S. Food and Drug Administration (FDA), in October of 2006, for the treatment of patients with cutaneous T-cell lymphoma (CTCL) who have progressive, persistent or recurrent disease on or following two systemic therapies. Of 25 patients receiving oral vorinostat in a Phase I study of hematologic malignancies, 12 had DLBCL. One patient with DLBCL had a partial response (PR), one with transformed DLBCL had a complete response (CR) and one patient with cutaneous T-cell lymphoma had a PR. (10) Chief side effects were dehydration, fatigue, anorexia, and diarrhea. The pivotal Phase II trial in refractory cutaneous T-cell lymphoma showed a 24% response rate, all partial responses, leading to approval of vorinostat for this indication. (11) Phase II trials are ongoing in relapsed or refractory lymphoma (NHL) but suggest modest single-agent activity and likely cytostatic response. In a Phase II trial of relapsed/refractory DLBCL following at least two systemic therapies, vorinostat was given at doses of 300 mg twice daily for 14 of 21 days, and was reduced to 3 days per week due to toxicity (Grade 3 muscle spasms and Grade 3-4 thrombocytopenia, n=3). Other Grade 3-4 toxicities included asthenia (n=2). Of 18 patients enrolled, one had a CR and one had stable disease (SD). (12) A SWOG Phase II study of PXD101, an intravenous HDAC inhibitor, for patients with relapsed DLBCL has recently closed. There was one Grade 4 lymphopenia and one Grade 4 fatigue and muscle weakness in 18 patients evaluable for toxicity. A Phase II study of vorinostat at 200 mg twice daily for 14 of 21 days in relapsed/refractory indolent NHL demonstrated 6 CRs and 4 PRs in 35 patients, with median PFS of 7 months. Four patients stopped due to toxicity – fatigue and diarrhea (1), diarrhea and dizziness (2), and deep venous thrombosis (1). (13) A Phase II SWOG trial of vorinostat in relapsed/refractory Hodgkin lymphoma, S0517, recently closed with four Grade 4 hematologic toxicities in 27 patients, three with thrombocytopenia and one with anemia. Vorinostat demonstrated synergy with rituximab in NHL B-cell lines and SCID mouse model. In SUDHL-4 and Daudi cell lines, the combination induced apoptosis by downregulating Bcl-2/Bcl-XL, inhibited NF-kB activity, and downregulated c-myc. Vorinostat-rituximab induced apoptosis in primary lymphoma cell lines in three patients, and significantly prolonged survival in SCID mice injected with Daudi cells. (14) There is evidence for synergy between vorinostat and anthracyclines. Vorinostat revealed synergy with doxorubicin in HL cell lines. (15) In breast and other solid tumor cell lines, pre-treatment with vorinostat was necessary for potentiation of topoisomerase II inhibitor effects. In that study, 48 hours of pretreatment were necessary for a full synergistic effect. (16) Subsequent Phase I study of vorinostat for 3 days followed by doxorubicin on Day 3, on 3 out of 4 weeks, reached MTD at 400 mg PO BID (Grade 3 nausea/vomiting [2 out of 6] and fatigue [1 out of 6] at 1,000 mg) with 2 partial responses in 24 evaluable patients. (17) However, simultaneous 3-day treatment of acute lymphocytic leukemia (ALL) cell line MOLT4 and fresh ALL cells with vorinostat and idarubicin produced at least an additive effect in inducing apoptosis, without evidence of antagonism. Additionally, the results were no different if the intervals between drug administrations were 4 hours or 24 hours. (18) A Phase I trial of vorinostat and idarubicin on Days 1-3 in patients with acute leukemia reached MTD of vorinostat at 400 mg PO TID, resulting in one complete response, one complete response without platelet recovery, and three marrow responses in 26 patients. (19)

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Several Phase I studies addressed adding vorinostat to combination chemotherapy. In a dose-escalation trial of 28 patients with solid tumors, 23 of which received no prior therapy, vorinostat on Days 1-14 was combined with paclitaxel 175-200 mg/m2 and carboplatin AUC 6 on Day 1. Dose limiting toxicity (DLT) was observed in 2 of 12 patients at 400 mg daily dose (Grade 3 vomiting and Grade 4 febrile neutropenia). Prominent hematologic toxicities included thrombocytopenia (seven Grade 3, four Grade 4) and neutropenia (eight Grade 3, fourteen Grade 4, two febrile neutropenia), with anemia being less significant (three Grade 3, no Grade 4). (20) Vorinostat (SAHA) was also effectively combined with FOLFOX for metastatic colorectal cancer at 300 mg twice daily every 1 of 2 weeks. (21) The Phase I portion of this study will address the safety of combining vorinostat (SAHA) with standard therapy in DLBCL. R-CHOP chemotherapy is the standard of care for treatment of newly diagnosed DLBCL. Based on the above, a Phase II trial combining vorinostat (SAHA) with R-CHOP in patients with newly diagnosed DLBCL is warranted to improve their PFS. The appropriate DLBCL population would be the patients with decreased progression-free survival (PFS). According to a favorable estimate based on British Columbia Cancer Agency data, patients with revised International Prognostic Index (based on a uniform population of R-CHOP-treated patients) of 0 had a 94% 4-yr PFS, while those with 1-2 factors had 80% 4-year PFS, and those with 3-5 factors had 53% 4-year PFS. (22) Data from longer follow-up of prospective GELA and U.S. Intergroup trials are less sanguine, with less than 50% failure-free or event-free survival at 6 years. (23,24) Therefore, patients with IPI or R-IPI of > 0 should benefit from improvements in therapy. Translational Medicine Studies Objective #1: To assess whether pre-treatment acetylation status of histones, expression of MHC Class II genes, and/or percentage of CD8+ tumor infiltrating lymphocytes (TIL) correlate with progression-free survival. To assess the importance of MHC class II protein expression, we will perform imunohisto-chemistry (IHC) on pre-treatment paraffin sections to evaluate the expression of MHC class II proteins HLA-DR, -DP, and DQ. Alternatively, quantitative nuclease protection assay (qNPA) can be used to assess the expression of MHC class II proteins in a more quantitative fashion. (25) The master transactivator CIITA cannot be evaluated by IHC, so the presence of CIITA mRNA will be assessed by quantitative RT-PCR. CD8 staining will quantify the percentage of tumor-infiltrating lymphocytes (as in our previous publications). Global acetylation status will be determined by IHC using antibodies for acetylated H3 and H4. The results will then be correlated to progression-free survival (and secondary endpoints such as overall survival and response). Objective #2: To explore whether treatment with vorinostat-R-CHOP increases histone acetylation, alters expression of MHC class II proteins, or alters percentage of T-cell subsets (CD8+, CD4+, FOXP3+) or infiltrating macrophages. We will request optional paraffin needle core biopsy specimens to be obtained at cycle 1, day 9, to be matched to pre-treatment paraffin specimens. The effect of vorinostat-R-CHOP treatment on global acetylation status will be determined by IHC using antibodies for acetylated H3 and H4. Change in MHC class II protein expression will be assessed by IHC, or alternatively by qNPA. RT-PCR will be used to quantitate changes in CIITA mRNA levels. IHC for CD8, CD3, CD4, FoxP3, and CD68 will be used to assess the changes in T-cell subsets and infiltrating macrophages. The changes will then be correlated to progression-free survival (and secondary endpoints such as overall survival and response). Objective #3: To explore whether histone acetylation status of tumor tissues correlates with MHC class II expression of peripheral blood B cells and lymphocyte subsets. Whole blood specimens will be requested from all institutions on days 1 and 9 of cycle 1. Flow cytometry will be used to first gate on CD20+ B cells and then to quantitatively evaluate staining for HLA-DR on the B cells and the lymphocyte subset makeup. Flow cytometry will also be used to assess quantitatively the global acetylation status of peripheral blood B cells by measuring acetylated H3 and H4. Peripheral blood and tissue results will then be correlated.

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Objective #4: To explore whether the change in systemic levels of immune cytokines with vorinostat-R-CHOP correlates with lymphoma symptoms, response, progression-free or overall survival. Serum specimens will be requested from all institutions on days 1 and 9 of cycle 1. The effects of treatment on systemic levels of 30 pro- and anti-inflammatory cytokine and immune factors will be evaluated by cytokine bead array analysis using Luminex X-MAP bead array technology. Presence of pruritus and systemic symptoms at baseline, and/or their resolution on therapy will be correlated to cytokine and immune factor levels and changes in these levels. Furthermore, baseline levels and changes in the levels of immune cytokines will be correlated with response, PFS, and OS. Inclusion of Women and Minorities This study was designed to include women and minorities, but was not designed to measure differences of intervention effects. The table below captures targeted/planned enrollment by gender, ethnic and racial categories.

Accrual Targets

Sex/Gender Ethnic Category Females Males Total

Hispanic or Latino 3 + 3 = 6

Not Hispanic or Latino 43 + 46 = 89

Ethnic Category: Total of all subjects

46 + 49 = 95

Racial Category

American Indian or Alaskan Native 1 + 1 = 2

Asian 1 + 1 = 2

Black or African American 3 + 3 = 6

Native Hawaiian or other Pacific Islander 0 + 0 = 0

White 41 + 44 = 85

Racial Category: Total of all subjects

46 + 49 = 95

3.0 DRUG INFORMATION 3.1 Cyclophosphamide (Cytoxan®) (NSC-26271)

a. DESCRIPTION

2-[bis (2-chloroethyl) amino] tetrahydro-2H-1, 3,2-oxazaphosphorine 2-oxide monohydrate. Cyclophosphamide is biotransformed principally in the liver to active alkylating metabolites, which cross-link to tumor cell DNA.

b. TOXICOLOGY

Human Toxicology: Toxicity from cyclophosphamide includes bone marrow suppression which usually occurs 10 to 12 days after administration, nausea, vomiting, anorexia, abdominal discomfort, diarrhea, stomatitis, hemorrhagic colitis, jaundice, reversible alopecia, hemorrhagic cystitis which can frequently be prevented with increased hydration, hematuria, ureteritis, tubular necrosis,

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fibrosis of the bladder, cardiac toxicity which may potentiate doxorubicin-induced cardiotoxicity, rare anaphylactic reaction, skin rash, hyperpigmentation of the skin and nails, interstitial pulmonary fibrosis, and cross sensitivity with other alkylating agents. Treatment with cyclophosphamide may cause significant suppression of the immune system. With the combination therapy the most frequent adverse event observed to date is neutropenia. Prophylactic G-CSF for subsequent cycles has been necessary. Dose reductions have been necessary for neutropenia and mucositis.

Second malignancies, most frequently of the urinary bladder and hematological systems, have been reported when cyclophosphamide is used alone or with other anti-neoplastic drugs. It may occur several years after treatment has been discontinued. Increased myelosuppression may be seen with chronic administration of high doses of phenobarbital. Cyclophosphamide inhibits cholinesterase activity and potentiates effect of succinylcholine chloride. If patient requires general anesthesia within 10 days after cyclophosphamide administration, the anesthesiologist should be alerted. Adrenal insufficiency may be worsened with cyclophosphamide. The occurrence of acute leukemia has been reported rarely in patients treated with anthracycline/alkylator combination chemotherapy. For prescribing information and a comprehensive list of adverse events associated with cyclophosphamide, please refer to the drug package insert.

c. PHARMACOLOGY

Pharmacokinetics: Cyclophosphamide is activated principally in the liver by a mixed function microsomal oxidase system. PO administration is well absorbed, with bioavailability greater than 75%. Five to twenty-five percent of unchanged drug is excreted in the urine. Several active and inactive metabolites have been identified with variable plasma protein binding. There appears to be no evidence of clinical toxicity in patients with renal failure, although elevated levels of metabolites have been observed. Formulation: Cyclophosphamide is supplied in 100 mg, 200 mg, 500 mg, 1 gram and 2 gram vials as a white powder. The drug should be reconstituted with Sterile Water for Injection, USP, and may be diluted in either normal saline or D5W.

Storage and Stability: Although the reconstituted cyclophosphamide is stable for six days under refrigeration, it contains no preservatives and therefore should be used within 6 hours. Administration: The drug should be diluted in about 150 cc of normal saline or D5W and infused IV. An added dose of IV fluids may help prevent bladder toxicity. Supplier: This drug is commercially available for purchase by a third party. This drug will not be supplied by the NCI.

3.2 Doxorubicin (Adriamycin) (NSC-123127)

a. DESCRIPTION

Doxorubicin is a cytotoxic anthracycline antibiotic different from daunorubicin by the presence of a hydroxyl group in the C-14 position. Doxorubicin is produced by fermentation from S. Peucetius var. caesius. Its mechanism of action is thought to be the binding of nucleic acids, preventing DNA and possibly RNA synthesis.

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b. TOXICOLOGY

Human Toxicology: Studies with doxorubicin have shown that the major toxic effects of this drug are alopecia, which is often total but always reversible; nausea and vomiting, which develops shortly after drug administration, occasionally persisting for 2 - 3 days; fever on the day of administration; and phlebitis at the site of the drug's injection. Extravasation of the drug will lead to soft tissue necrosis. Phlebosclerosis, cellulitis, vesication and erythematous streaking have also been seen. Mucositis may be seen 5 - 10 days after administration. Ulceration and necrosis of the colon, particularly the cecum, with bleeding and severe infection have been reported with concomitant administration of cytarabine. Anorexia and diarrhea have also been observed. Hyperpigmentation of nailbeds and dermal creases, onycholysis and recall of skin reaction from prior radiotherapy may occur. Cardiac toxicity manifested as acute left ventricular failure, congestive heart failure, arrhythmia or severe cardiomyopathy has been reported, but appears to occur predominantly in patients who receive total doses in excess of 550 mg/m2. Myelosuppression, predominantly neutropenia, is common with nadir occurring approximately two weeks after a single injection; lesser degrees of anemia and thrombocytopenia have been reported. Rapid recovery of the blood counts approximately two and a half weeks after a single injection generally permits an every three week schedule. Patients with obstructive liver disease have more severe myelosuppression due to impaired drug excretion. Thus, patients with hepatic dysfunction may need to have reduced dosage or to be excluded from therapy. Renal excretion of doxorubicin is minimal, but enough to color the urine red; thus impaired renal function does not appear to increase the toxicity of doxorubicin. Other side effects include fever, chills, facial flushing, itching, anaphylaxis, conjunctivitis and lacrimation. The occurrence of acute leukemia has been reported rarely in patients treated with anthracycline/alkylator combination chemotherapy. For prescribing information and a comprehensive list of adverse events associated with doxorubicin, please refer to the drug package insert.

c. PHARMACOLOGY

Kinetics: Intravenous administration is followed by a rapid plasma clearance with significant tissue binding. Urinary excretion is negligible; biliary excretion accounts for 40 to 50% of the administered dose being recovered in the bile or the feces in 7 days. The drug does not cross the blood-brain barrier. Formulation: Doxorubicin is supplied in 10, 20 and 50 mg single-use vials, and 150 mg multidose vials as a red-orange, lyophilized powder which has a storage stability of at least two years - see expiration date on vial. Doxorubicin should be reconstituted with 5, 10, 25 and 75 ml respectively, of Sodium Chloride Injection, USP (0.9%) to give a final concentration of 2 mg/mL.

Storage and Stability: The reconstituted doxorubicin is stable for 24 hours at room temperature and 48 hours under refrigeration (2°-8°C). It should be protected from exposure to sunlight. Discard any unused solution from the vials. Bacteriostatic diluents with preservatives are NOT recommended as they might possibly worsen the reaction to extravasated drug.

Administration: Doxorubicin may be further diluted in 5% dextrose or sodium chloride injection and should be administered slowly into tubing of a freely flowing intravenous infusion with great care taken to avoid extravasation.

Supplier: Doxorubicin is commercially available and should be purchased by a third party. Doxorubicin will not be supplied by the NCI.

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3.3 Prednisone (NSC-10023)

a. DESCRIPTION Prednisone is a glucocorticoid rapidly absorbed from the GI tract.

b. TOXICOLOGY Human Toxicology: Possible adverse effects associated with the use of prednisone are: fluid and electrolyte disturbances, congestive heart failure in susceptible persons, hypertension, euphoria, personality changes, insomnia, mood swings, depression, exacerbation of infection (e.g., tuberculosis), exacerbation or symptoms of diabetes, psychosis, muscle weakness, osteoporosis, vertebral compression fractures, pancreatitis, esophagitis, peptic ulcer, dermatologic disturbances, convulsions, vertigo and headache, endocrine abnormalities, ophthalmic changes, and metabolic changes. Some patients have experienced itching and other allergic, anaphylactic or other hypersensitivity reactions. Withdrawal from prolonged therapy may result in symptoms including fever, myalgia and arthralgia. Phenytoin, phenobarbital, and ephedrine enhance metabolic clearance of corticosteroids. Corticosteroids should be used cautiously in patients with hypothyroidism, cirrhosis, ocular herpes simplex, existing emotional instability or psychotic tendencies, nonspecific ulcerative colitis, diverticulitis, fresh intestinal anastomoses, peptic ulcer, renal insufficiency, hypertension, osteoporosis and myasthenia gravis. Immunization procedures (especially smallpox vaccination) should not be undertaken in patients on corticosteroids. For prescribing information and a comprehensive list of adverse events associated with prednisone please refer to the drug package insert.

c. PHARMACOLOGY Pharmacokinetics: Natural and synthetic glucocorticoids are readily and completely absorbed from the GI tract. Prednisone is very slightly soluble in water. Glucocorticoids have salt-retaining properties. The anti-inflammatory property of this drug is its ability to modify the body's immune system. On the other hand, glucocorticoids suppress the body's response to viral as well as bacterial infections. Formulation: Prednisone is available in 2.5 mg, 5 mg, 10 mg, 20 mg and 50 mg tablets. Storage and Stability: Prednisone should be stored at room temperature. Administration: Prednisone is administered orally. Supplier: Prednisone is commercially available and should be purchased by third party. Prednisone will not be supplied by the NCI.

3.4 Rituximab Chimeric Monoclonal anti-CD20 Antibody (IDEC-C2B8) (NSC-687451) a. DESCRIPTION

Rituximab is a mouse/human chimeric monoclonal antibody consisting of human IgG1 heavy and kappa light chain constant regions with murine variable regions from the murine IgG1 kappa anti-human CD20 monoclonal antibody rituximab. The rituximab antibody is produced by a Chinese hamster ovary transfectoma.

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b. TOXICOLOGY

Human Toxicology: Single doses of up to 500 mg/m2 and weekly x 4 doses of 375 mg/m2 have been administered without dose limiting toxicity. Adverse events are most common during the initial antibody infusion and usually consist of Grade I or 2 fever (73%), asthenia (16%) chills (38%) nausea (19%), vomiting (11%), rash (14%) and tumor site pain (3%). Grade 1 or 2 hypotension (8%) may be treated with IV fluids. Hematologic toxicity is usually mild and reversible. Transient decreases in the WBC or platelet count have been observed - especially in patients with high levels of circulating tumor cells or bone marrow involvement. Two patients have had late-onset Grade 4 neutropenia at four and ten months that was attributed to an unknown cause, was transient and resolved. Infections (Grade 1 and 2) have not been related to dose level. Symptoms are generally associated with the initial antibody infusions and diminish in frequency with each successive infusion. A report in the literature described an increase in fatal infection in HIV-related lymphoma patients when rituximab was used in combination with CHOP chemotherapy as compared to CHOP alone. In patients with Waldenstrom’s macroglobulinemia, following initiation of rituximab therapy, transient increases in serum IgM levels have been observed which may result in hyperviscosity syndrome requiring plasmapheresis. Severe Infusion and Hypersensitivity Reactions: Rituximab has caused severe infusion reactions. In some cases, these reactions were fatal. An infusion-related symptom complex consisting of fever and chills/rigors has occurred in the majority of patients during the first rituximab infusion. Signs and symptoms of severe infusion reactions may include urticaria, hypotension, angioedema, hypoxia, or bronchospasm. The most severe manifestations and sequelae include pulmonary infiltrates, acute respiratory distress syndrome, myocardial infarction, ventricular fibrillation, cardiogenic shock, and anaphylactic and anaphylactoid events. These reactions generally occurred within 30 minutes to 2 hours of beginning the first infusion, and resolved with slowing or interruption of the rituximab infusion and with supportive care (including, but not limited to IV saline, diphenhydramine, and acetaminophen). Tumor Lysis Syndrome: Rituximab rapidly decreases benign and malignant CD20 positive cells. Tumor lysis syndrome has been reported to occur within 12 to 24 hours after the first rituximab infusion in patients with high numbers of circulating malignant lymphocytes. Patients with high tumor burden (bulky lesions) may also be at risk. Patients at risk for developing tumor lysis syndrome should be followed closely and appropriate laboratory monitoring performed. Hepatitis B Reactivation with Related Fulminant Hepatitis and Other Viral Infections: Hepatitis B virus (HBV) reactivation with fulminant hepatitis, hepatic failure, and death has been reported in some patients with hematologic malignancies treated with rituximab. The majority of patients received rituximab in combination with chemotherapy. The median time to the diagnosis of hepatitis was approximately 4 months after the initiation of rituximab and approximately one month after the last dose. Persons at high risk of HBV infection should be screened before initiation of rituximab. Carriers of hepatitis B should be closely monitored for clinical and laboratory signs of active HBV infection and for signs of hepatitis during and for up to several months following rituximab therapy. In patients who develop vial hepatitis, rituximab and any concomitant chemotherapy should be discontinued and appropriate treatment including antiviral therapy initiated. There are insufficient data regarding the safety of resuming rituximab therapy in patients who develop hepatitis subsequent to HBV reactivation.

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The following additional serious viral infections, either new, reactivated or exacerbated, have been identified in clinical studies or postmarketing reports. The majority of patients received rituximab in combination with chemotherapy or as part of a hematopoietic stem cell transplant. These viral infections included JC virus (progressive multifocal leukoencephalopathy [PML]), cytomegalovirus, herpes simplex virus, parvovirus B19, varicella zoster virus, West Nile virus, and hepatitis C. In some cases, the viral infections occurred up to one year following discontinuation of rituximab and have resulted in death.

Severe Mucocutaneous Reactions: Mucocutaneous reactions, some with fatal outcome, have been reported in patients treated with rituximab. These reports included paraneoplastic pemphigus (an uncommon disorder which is a manifestation of the patient's underlying malignancy), Stevens-Johnson syndrome, lichenoid dermatitis, vesiculobullous dermatitis, and toxic epidermal necrolysis. The onset of the reaction in the reported cases has varied from 1-13 weeks following rituximab exposure. Patients experiencing a severe mucocutaneous reaction should not receive any further infusions and seek prompt medical evaluation. Skin biopsy may help to distinguish among different mucocutaneous reactions and guide subsequent treatment. The safety of readministration of rituximab to patients with any of these mucocutaneous reactions has not been determined.

Bowel Obstruction and Perforation: Abdominal pain, bowel obstruction and perforation, in some cases leading to death, were observed in patients receiving rituximab in combination with chemotherapy for DLBCL. In post-marketing reports, which include both patients with low-grade or follicular NHL and DLBCL, the mean time to onset of symptoms was 6 days (range 1-77) in patients with documented gastrointestinal perforation. Complaints of abdominal pain, especially early in the course of treatment, should prompt a thorough diagnostic evaluation and appropriate treatment.

Cardiovascular: The incidence of serious cardiovascular events in the double-blind clinical trial for rheumatoid arthritis (RA) patients was 1.7% and 1.3% in rituximab and placebo groups, respectively. Three cardiovascular deaths occurred during the double-blind period of the RA studies, including all rituximab regimens (3/759 = 0.4%) as compared to none in the placebo group (0/389).

Since patients with RA are at increased risk for cardiovascular events compared to the general population, patients with RA should be monitored throughout the infusion and rituximab should be discontinued in the event of a serious or life-threatening cardiac event.

Rituximab infusions should be discontinued in the event of serious or life-threatening cardiac arrhythmias. Patients who develop clinically significant arrhythmias should undergo cardiac monitoring during and after subsequent infusions of rituximab. Patients with pre-existing cardiac conditions including arrhythmias and angina have had recurrences of these events during rituximab therapy and should be monitored throughout the infusion and immediate post-infusion period. Renal: Rituximab administration has been associated with severe renal toxicity including acute renal failure requiring dialysis and in some cases, has led to a fatal outcome in hematologic malignancy patients. Renal toxicity has occurred in patients with high numbers of circulating malignant cells (> 25,000/mm3) or high tumor burden who experience tumor lysis syndrome and in patients with NHL administered concomitant cisplatin therapy during clinical trials. The combination of cisplatin and rituximab is not an approved treatment regimen. If this combination is used in clinical trials extreme caution should be exercised; patients should be monitored closely for signs of renal failure. Discontinuation of rituximab should be considered for those with rising serum creatinine or oliguria.

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Immunization: The safety of immunization with live viral vaccines following rituximab therapy has not been studied and vaccination with live virus vaccines is not recommended. The ability to generate a primary or anamnestic humoral response to vaccination is currently being studies. For patients with NHL, the benefits of primary and/or booster vaccinations should be weighed against the risks of delay in initiation of rituximab therapy. Carcinogenesis, Impairment of Fertility, Pregnancy, and Nursing: No long-term animal studies have been performed to establish the carcinogenic potential of rituximab. Studies also have not been completed to assess mutagenic potential of rituximab, or to determine potential effects on fertility in males or females. Individuals of childbearing potential should use effective contraceptive methods during treatment and for up to 12 months following rituximab therapy. It is not known whether rituximab is excreted in human milk. Because human IgG is excreted in human milk and the potential for absorption and immunosuppression in the infant is unknown, women should be advised to discontinue nursing until circulating drug levels are no longer detectable. Comprehensive Adverse Events and Potential Risks list (CAEPR) For Rituximab (NSC 687451) The Comprehensive Adverse Event and Potential Risks list (CAEPR) provides a single list of reported and/or potential adverse events (AE) associated with an agent using a uniform presentation of events by body system. In addition to the comprehensive list, a subset, the Agent Specific Adverse Event List (ASAEL), appears in a separate column and is identified with bold and italicized text. This subset of AEs (ASAEL) contains events that are considered 'expected' for expedited reporting purposes only. Refer to the 'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' http://ctep.info.nih.gov/protocolDevelopment/default.htm#adverse_events_adeers for further clarification. Frequency is provided based on 986 patients. Below is the CAEPR for Rituximab.

Version 2.1, March 19, 20101

Adverse Events with Possible

Relationship to Rituximab (CTCAE 4.0 Term)

[n= 986]

EXPECTED AEs

FOR ADEERS REPORTING

Agent Specific Adverse Event List

(ASAEL)

Likely (>20%) Less Likely (<=20%) Rare but Serious (<3%)

Expected

BLOOD AND LYMPHATIC SYSTEM DISORDERS Anemia Anemia Blood and lymphatic

system disorders - Other (Hyperviscosity: Waldenstrom’s)

Blood and lymphatic system disorders - Other (Hyperviscosity: Waldenstrom’s)

Febrile neutropenia Febrile neutropeniaCARDIAC DISORDERS Myocardial infarction Myocardial

infarction Sinus tachycardia Sinus tachycardia Supraventricular

tachycardia Supraventricular

tachycardia

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GASTROINTESTINAL DISORDERS Abdominal pain Abdominal pain Diarrhea Diarrhea Nausea Nausea Vomiting Vomiting GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS

Chills Chills Edema limbs Fatigue Fatigue Fever Fever Infusion related reaction

Infusion related reaction

Pain IMMUNE SYSTEM DISORDERS Allergic reaction Allergic reaction Anaphylaxis Serum sickness Serum sickness INFECTIONS AND INFESTATIONS Infection2 Infection2

Infections and infestations - Other (Activation of Hepatitis B, C, CMV, parvovirus B19, JC virus, varicella zoster, herpes simplex, West Nile virus)

Infections and infestations - Other (Activation of Hepatitis B, C, CMV, parvovirus B19, JC virus, varicella zoster, herpes simplex, West Nile virus)

Infections and infestations - Other (Infection in HIV Positive Patients)

INVESTIGATIONS Lymphocyte count decreased

Lymphocyte count decreased

Neutrophil count decreased


Platelet count decreased


White blood cell decreased


METABOLISM AND NUTRITION DISORDERS Hyperglycemia Hypocalcemia Hypocalcemia Hypokalemia Tumor lysis

syndrome Tumor lysis syndrome

MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS Arthralgia Arthralgia Back pain Myalgia Myalgia NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS)

Tumor pain Tumor pain

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NERVOUS SYSTEM DISORDERS Dizziness Dizziness Headache Headache Lethargy Nervous system

disorders - Other (progressive multifocal leukoencepha-lopathy)

Seizure Seizure RENAL AND URINARY DISORDERS Acute kidney injury RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS Adult respiratory

distress syndrome

Allergic rhinitis Bronchospasm Bronchospasm Cough Cough Dyspnea Dyspnea Hypoxia Hypoxia Pneumonitis Pneumonitis Sore throat SKIN AND SUBCUTANEOUS TISSUE DISORDERS Erythema

multiforme Erythema multiforme

Hyperhidrosis Hyperhidrosis Pruritus Pruritus Rash maculo-papular Rash maculo-

papular Skin and subcutaneous

tissue disorders - Other (angioedema)

SKIN AND SUBCUTANEOUS TISSUE DISORDERS (contd.) Stevens-Johnson

syndrome Stevens-Johnson syndrome

Toxic epidermal necrolysis

Toxic epidermal necrolysis

Urticaria Urticaria VASCULAR DISORDERS Flushing Flushing Hypertension Hypertension Hypotension Hypotension 1 This table will be updated as the toxicity profile of the agent is revised.

Updates will be distributed to all Principal Investigators at the time of revision. The current version can be obtained by contacting [email protected]. Your name, the name of the investigator, the protocol and the agent should be included in the e-mail.

2 Infection includes all 75 sites of infection under the INFECTIONS AND INFESTATIONS SOC.

3 Gastrointestinal obstruction includes Colonic obstruction, Duodenal obstruction, Esophageal obstruction, Ileal obstruction, Jejunal obstruction, Obstruction gastric, Rectal obstruction, and Small intestinal obstruction under the GASTROINTESTINAL DISORDERS SOC.

4 Gastrointestinal perforation includes Colonic perforation, Duodenal perforation, Esophageal perforation, Gastric perforation, Ileal perforation, Jejunal perforation, Rectal perforation, and Small intestinal perforation under the GASTROINTESTINAL DISORDERS SOC.

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Also reported on rituximab trials but with the relationship to rituximab still undetermined: BLOOD AND LYMPHATIC SYSTEM DISORDERS - Bone marrow hypocellular; Hemolysis CARDIAC DISORDERS - Atrial fibrillation; Atrial flutter; Cardiac disorders - Other (cyanosis); Left ventricular systolic dysfunction; Sinus bradycardia; Ventricular fibrillation EYE DISORDERS - Conjunctivitis; Eye disorders - Other (ocular edema); Uveitis; Watering eyes GASTROINTESTINAL DISORDERS - Constipation; Dyspepsia; Dysphagia; Gastrointestinal obstruction3; Gastrointestinal perforation4; Mucositis oral GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Flu like symptoms; Non-cardiac chest pain INFECTIONS AND INFESTATIONS - Infections and infestations - Other (Opportunistic infection associated with >=Grade 2 Lymphopenia) INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Fracture INVESTIGATIONS - Alkaline phosphatase increased; Aspartate aminotransferase increased; Blood bilirubin increased; Cardiac troponin I increased; Cardiac troponin T increased; Creatinine increased; Investigations - Other (hyperphosphatemia); Investigations - Other (LDH increased); Weight loss METABOLISM AND NUTRITION DISORDERS - Anorexia; Hypercalcemia; Hyperkalemia; Hypermagnesemia; Hypernatremia; Hyperuricemia; Hypoglycemia; Hypomagnesemia; Hyponatremia MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthritis NERVOUS SYSTEM DISORDERS - Nervous system disorders - Other (Cranial Neuropathy NOS); Peripheral motor neuropathy; Peripheral sensory neuropathy; Pyramidal tract syndrome; Reversible posterior leukoencephalopathy syndrome; Syncope PSYCHIATRIC DISORDERS - Agitation; Anxiety; Depression; Insomnia RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Epistaxis; Pharyngolaryngeal pain; Pleural effusion; Pulmonary edema; Respiratory, thoracic and mediastinal disorders - Other (bronchiolitis obliterans) SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Skin and subcutaneous tissue disorders - Other (paraneoplastic pemphigus) VASCULAR DISORDERS - Phlebitis; Thromboembolic event; Vasculitis Note: Rituximab in combination with other agents could cause an exacerbation of any adverse event currently known to be caused by the other agent, or the combination may result in events never previously associated with either agent.

c. PHARMACOLOGY Pharmacokinetics: In prior studies patients treated at the 375 mg/m2 dose levels exhibited detectable antibody concentrations throughout the treatment period. Most patients exhibited increasing pre-infusion antibody concentrations with each subsequent infusion. In nine patients, the T1/2 following the first antibody infusion was 59.8 hours (11.1-104.6 hr) with a Cmax of 271 mcg/mL. Following the fourth antibody infusion when circulating B cells had been depleted and antigenic sites coated, the T 1/2 was 174 hr (26.4-442.3 hr) and Cmax 496.7 mcg/mL.

Formulation: Rituximab antibody will be provided in 100 mg (10 mL) and 500 mg (50 ml) pharmaceutical grade vials at a concentration of 10 mg of protein per mL (actual concentration should be noted on the product label).

Storage and Stability: Rituximab should be stored at 2 - 8°C. Do not freeze or store at room temperature. The product is a protein- HANDLE GENTLY AND AVOID FOAMING. The avoidance of foaming during product handling, preparation and administration is important, as foaming may lead to the de-naturing of the product proteins.

S0806 Page 16

Administration: Prepare the rituximab infusion solution as follows: 1. If a delay in administration of the infusion occurs after the product is

prepared, the properly identified container may be kept refrigerated at 2 - 8°C for up to six hours.

2. Use sterile, non-pyrogenic, disposable containers, syringes, needles,

stopcocks and transfer tubing, etc. 3. Transfer of the rituximab from the glass vial should be made by using a

suitable sterile graduated syringe and large gauge needle. 4. Transfer the appropriate amount of rituximab from the graduated syringe,

into a partially filled IV pack containing sterile, pyrogen-free 0.9% sodium chloride solution, USP (saline solution). The final concentration of rituximab in saline solution should be a concentration of 1 mg/ml - 4 mg/ml. Mix by inverting the bag gently. DO NOT USE A VACUUM APPARATUS to transfer the product from the syringe to the plastic bag.

5. Place an IV administration set into the outflow port of the bag containing

the infusion solution.

6. NOTE: DO NOT USE evacuated glass containers which require vented administration sets because this causes foaming as air bubbles pass through the solution.

The administration of rituximab will be accomplished by slow IV infusion. CAUTION: DO NOT ADMINISTER AS AN INTRAVENOUS PUSH OR BOLUS. IV pumps such as the IMED 960 may be used with the rituximab infusion. DO NOT INFUSE CONCOMITANTLY with another IV solution or IV medications. Prime the line with the rituximab solution such that approximately 30 mL are delivered. This will saturate the filter and tubing.

Supplier: This drug is commercially available for purchase by a third party. This drug will not be supplied by the NCI.

3.5 Vincristine (Oncovin) (NSC-67574)

a. DESCRIPTION

Chemistry: Vincristine is one of the so-called vinca-alkaloids and is extracted from the plant cantharanthus roseus (vinca rosea).

Biochemistry: This drug appears to produce the arrest of mitosis in animal cells by interfering with microtubule function.

b. TOXICOLOGY

Human Toxicology: The primary toxic effects of vincristine are neurological with paresthesia, weakness, muscle wasting, motor difficulties including difficulty walking and slapping gait, loss of deep tendon reflexes, sensory loss, neuritic pain, paralytic ileus, bladder atony, and constipation. Rarely, it produces myelosuppression. Other side effects may include alopecia, allergic reactions, (including rare anaphylaxis, rash and edema), jaw pain, hypertension, hypotension, nausea, vomiting, diarrhea, fever, headache, oral ulceration, optic atrophy with blindness, ptosis, diplopia and photophobia. The occurrence of acute leukemia has been reported rarely in patients treated with anthracycline/alkylator combination chemotherapy. For prescribing information and a comprehensive list of adverse events associated with vincristine please refer to the drug package insert.

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c. PHARMACOLOGY

Pharmacokinetics: After IV administration, a triphasic serum decay pattern follows with half-lives of 5 minutes, 2 - 3 hours, and 85 hours. The range of terminal half-life is 19 - 155 hours. Excretion is 80% in the feces and 10 - 20 % in the urine. The liver is the major excretory organ in humans and animals, and biliary obstruction causes increased toxicity in man. Formulation: 1 mg/1 mL, 2 mg/2 mL, and 5 mg/5 mL vials containing solution. It is also available in 1 mg/ mL and 2 mg/2 mL disposable syringes. Storage and Stability: It should be stored under refrigeration. Vincristine is available with and without preservatives so the time-frame for use once the vial has been entered varies. The intact vials have a labeled expiration date. Protect from light. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. Administration: Vincristine should be administered intravenously through a freely-running IV. If it extravasates, it produces a severe local reaction with skin slough. FATAL IF GIVEN INTRATHECALLY, FOR INTRAVENOUS USE ONLY. Supplier: Vincristine is commercially available, and should be purchased through a third party. This drug will NOT be supplied by the NCI.

3.6 Vorinostat (Suberoylanilide hydroxamic acid; SAHA) (NSC-701852) (IND-71976)

a. DESCRIPTION: Histone deacetylase (HDAC) inhibitor Histone deacetylases (HDACs) are a family of enzymes that regulate chromatin remodeling and gene transcription via the dynamic process of acetylation and deacetylation of core histones.

Vorinostat, a potent inhibitor of HDAC activity, binds directly to the catalytic pocket of HDAC enzymes. It causes G1 or G2 phase cell-cycle arrest, apoptosis, or differentiation in cultured transformed cells. Chemical Name: N-hydroxy-N’-phenyl-octane-1,8-diotic acid diamide; N-hydroxyl-N’phenyl (9CI) octanediamide; Other Names: Zolinza®, WIN 64652, MSK390, AP390

Classification: Antineoplastic CAS Registry Number: 149647-78-9 Molecular Formula: C14H20N203 Molecular Weight: 264.32

Approximate Solubility: Water ≤ 5 mg/mL

b. TOXICOLOGY

Human Toxicology: Studies with vorinostat have demonstrated that the tolerability of the drug appears to be determined by total daily dose and the length of consecutive days of dosing. The maximum tolerated dose (MTD) for continuous daily dosing without a rest period is 400 mg every day or 200 mg twice daily. The MTD for intermittent dosing is 300 mg twice daily x 3 consecutive days per week or 250 mg three times daily x 14 days followed by a 7-day rest.

S0806 Page 18 Revised 11/18/11

The most common dose limiting toxicities (DLTs) include anorexia, dehydration, diarrhea, nausea, vomiting, taste alteration (dysgeusia), fatigue, increased blood creatinine levels, hyperglycemia, hypocalcemia, hypokalemia, and anemia. The majority of these DLTs occurred within the first month on oral vorinostat. At continuous daily dosing of 600 mg every day, 300 mg twice daily, and 400 mg twice daily that exceeded the MTD, the pattern and severity of DLTs were similar. The DLTs were manageable because these toxicities resolved quickly after drug administration was interrupted. Vorinostat was found to be positive in both in vitro and in vivo genetic toxicity assays as it has mutagenicity properties and can induce chromosomal aberrations. Safe use of vorinostat in pregnancy has not been established. The possible effects on fertility have not been adequately evaluated. Safety in nursing women has not been proven. Comprehensive Adverse Events and Potential Risks List (CAEPR) for vorinostat (SAHA) (NSC #701852) The Comprehensive Adverse Event and Potential Risks list (CAEPR) provides a single list of reported and/or potential adverse events (AE) associated with an agent using a uniform presentation of events by body system. In addition to the comprehensive list, a subset, the Specific Protocol Exceptions to Expedited Reporting (SPEER), appears in a separate column and is identified with bold and italicized text. This subset of AEs (SPEER) is a list of events that are protocol specific exceptions to expedited reporting to NCI via AdEERS (except as noted below). Refer to the 'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf for further clarification. Frequency is provided based on 702 patients. Below is the CAEPR for vorinostat (SAHA). NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses next to the AE in the SPEER. If this CAEPR is part of a combination protocol using multiple investigational agents and has an AE listed on different SPEERs, use the lower of the grades to determine if expedited reporting is required.

Version 2.6, October 18, 20111

Adverse Events with Possible

Relationship to Vorinostat (SAHA) (CTCAE 4.0 Term)

[n= 702]

Specific Protocol

Exceptions to Expedited Reporting (SPEER)

(formerly known as ASAEL)

Likely (>20%) Less Likely (<=20%)

Rare but Serious (<3%)

BLOOD AND LYMPHATIC SYSTEM DISORDERS Anemia Anemia (Gr 2)

GASTROINTESTINAL DISORDERS Abdominal pain Constipation Constipation (Gr 2) Diarrhea Diarrhea (Gr 2)

Dry mouth Dry mouth (Gr 2) Dyspepsia Dyspepsia (Gr 2) Nausea Nausea (Gr 2) Vomiting Vomiting (Gr 2)


GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS

Fatigue Fatigue (Gr 2) Fever INFECTIONS AND INFESTATIONS Infection2 INVESTIGATIONS Alanine

aminotransferase increased

Alanine aminotransferase increased (Gr 2)

Alkaline phosphatase increased

Aspartate aminotransferase increased

Aspartate aminotransferase increased (Gr 2)

Blood bilirubin increased

Creatinine increased Creatinine increased (Gr 2) Lymphocyte count

decreased Lymphocyte count

decreased (Gr 2) Neutrophil count

decreased Neutrophil count decreased

(Gr 2) Platelet count decreased

Platelet count decreased (Gr 2)

Weight loss Weight loss (Gr 2) White blood cell

decreased White blood cell decreased

(Gr 2) METABOLISM AND NUTRITION DISORDERS Anorexia Anorexia (Gr 2)

Dehydration Dehydration (Gr 2) Hyperglycemia Hyperglycemia (Gr 2) Hypoalbuminemia Hypocalcemia Hypokalemia Hyponatremia Hypophosphatemia Hypophosphatemia (Gr 2) MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS

Musculoskeletal and connective tissue disorder - Other (muscle spasms)

Muscle weakness3 Muscle weakness3 (Gr 2)

NERVOUS SYSTEM DISORDERS Dizziness Dizziness (Gr 2) Dysgeusia Dysgeusia (Gr 2) RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS

Cough Cough (Gr 2) Dyspnea SKIN AND SUBCUTANEOUS TISSUE DISORDERS Alopecia Skin and

subcutaneous tissue disorders - Other (skin necrosis)


1 This table will be updated as the toxicity profile of the agent is revised. Updates will be distributed to all Principal Investigators at the time of revision. The current version can be obtained by contacting [email protected]. Your name, the name of the investigator, the protocol and the agent should be included in the e-mail.

2 Infection includes all 75 sites of infection under the INFECTIONS AND INFESTATIONS SOC.

3 Muscle weakness includes Generalized muscle weakness, Muscle weakness left-sided, Muscle weakness lower limb, Muscle weakness right-sided, Muscle weakness trunk, and Muscle weakness upper limb under the MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS SOC.

4 Prolongation of prothrombin time and International Normalized Ratio have been observed in patients using vorinostat concomitantly with coumarin-derivative anticoagulants.

Also reported on vorinostat (SAHA) trials but with the relationship to vorinostat (SAHA) still undetermined: BLOOD AND LYMPHATIC SYSTEM DISORDERS - Febrile neutropenia CARDIAC DISORDERS - Atrial fibrillation; Atrial flutter; Chest pain - cardiac; Left ventricular systolic dysfunction; Myocardial infarction; Palpitations; Pericardial effusion; Sinus bradycardia; Sinus tachycardia; Ventricular fibrillation EAR AND LABYRINTH DISORDERS - Tinnitus; Vertigo EYE DISORDERS - Blurred vision GASTROINTESTINAL DISORDERS - Abdominal distension; Anal hemorrhage; Bloating; Cheilitis; Colitis; Dysphagia; Esophageal hemorrhage; Esophagitis; Flatulence; Gastric hemorrhage; Gastritis; Gingival pain; Lower gastrointestinal hemorrhage; Mucositis oral; Oral hemorrhage; Small intestinal obstruction; Stomach pain; Upper gastrointestinal hemorrhage GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Chills; Death NOS; Edema limbs; Gait disturbance; General disorders and administration site conditions - Other (angioedema); General disorders and administration site conditions - Other (failure to thrive); Malaise; Multi-organ failure; Non-cardiac chest pain; Pain HEPATOBILIARY DISORDERS - Hepatic failure INFECTIONS AND INFESTATIONS - Infections and infestations - Other (Herpes zoster) INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Bruising; Vascular access complication; Wound dehiscence INVESTIGATIONS - Activated partial thromboplastin time prolonged4; Cardiac troponin I increased; Electrocardiogram QT corrected interval prolonged; GGT increased; INR increased4; Investigations - Other (elevated LDH); Lipase increased METABOLISM AND NUTRITION DISORDERS - Acidosis; Hypercalcemia; Hyperkalemia; Hypermagnesemia; Hypernatremia; Hypoglycemia; Hypomagnesemia; Tumor lysis syndrome MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthralgia; Back pain; Chest wall pain; Myalgia; Neck pain; Pain in extremity NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other (tumor hemorrhage); Tumor pain NERVOUS SYSTEM DISORDERS - Ataxia; Cognitive disturbance; Depressed level of consciousness; Dysphasia; Encephalopathy; Facial muscle weakness; Facial nerve disorder; Headache; Intracranial hemorrhage; Ischemia cerebrovascular; Lethargy; Memory impairment; Nervous system disorders - Other (Guillain-Barre syndrome); Nervous system disorders - Other (head injury); Nervous system disorders - Other (polyneuropathy); Paresthesia; Peripheral motor neuropathy; Peripheral sensory neuropathy; Seizure; Syncope; Tremor

S0806 Page 20a Revised 11/18/11

PSYCHIATRIC DISORDERS - Agitation; Anxiety; Confusion; Depression; Insomnia; Personality change; Psychosis RENAL AND URINARY DISORDERS - Acute kidney injury; Hematuria; Proteinuria; Urinary frequency; Urinary incontinence; Urinary retention; Urinary tract pain REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Pelvic pain; Uterine hemorrhage RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Bronchopulmonary hemorrhage; Epistaxis; Hypoxia; Nasal congestion; Pharyngeal mucositis; Pharyngolaryngeal pain; Pleural effusion; Pleuritic pain; Pneumonitis SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Dry skin; Hyperhidrosis; Nail loss; Palmar-plantar erythrodysesthesia syndrome; Pruritus; Purpura; Rash maculo-papular VASCULAR DISORDERS - Flushing; Hematoma; Hot flashes; Hypertension; Hypotension; Thromboembolic event; Vascular disorders - Other (arterial thrombosis); Vasculitis Note: Vorinostat (SAHA) in combination with other agents could cause an exacerbation of any adverse event currently known to be caused by the other agent, or the combination may result in events never previously associated with either agent. Patient Care Implications: Because vorinostat’s dose limiting toxicities are anorexia, dehydration, diarrhea, and fatigue, patients should maintain adequate fluid and food intake. Encourage patients to seek a nutritional consult.

S0806 Page 21

Treat diarrhea promptly with appropriate supportive care, including loperamide. Instruct patients to begin taking loperamide at the first signs of: 1) poorly formed or loose stool, 2) occurrence of more bowel movements than usual in one day, or 3) unusually high volume of stool. Loperamide should be taken in the following manner: 4 mg at first onset of diarrhea, then 2 mg after each unformed stool. Daily dose should not exceed 16 mg/day. Loperamide should not be taken prophylactically. Advise patients to drink plenty of clear fluids to help prevent dehydration caused by diarrhea. Avoid loperamide if there is the presence of blood or mucus in the stool or if diarrhea is accompanied by fever. If Grade 3 or 4 diarrhea develops, discontinue further treatment with vorinostat. Patients should not have taken valproic acid, another histone deacetylase inhibitor, for at least 2 weeks prior to study enrollment.

c. PHARMACOLOGY

Kinetics: The pharmacokinetics of oral vorinostat appears to be roughly linear at doses ranging from 200 mg to 600 mg. The absolute bioavailability of vorinostat under fasted (2 hour fast) or fed conditions was approximately 46%. Oral administration of vorinostat with food does not appear to substantially alter the rate or extent of absorption. Mean t1/2s of oral vorinostat (range: 92 to 150 minutes), were longer than the mean t1/2s after IV administration of the oral equivalent doses (range: 27 to 38 minutes), suggesting absorption rate limited disposition. Median Tmax values ranged from 45 minutes to 2.5 hours with no apparent relationship to dose. Potential Drug Interactions: The major pathways of vorinostat metabolism involve glucuronidation and β-oxidation. As vorinostat is not eliminated via CYP450 pathways, no drug-drug interactions are expected with known CYP450 inhibitors or inducers. Although vorinostat was not a potent reversible CYP450 inhibitor, studies performed to monitor gene expression changes indicated some potential for CYP2C9 and CYP3A4 activity suppression. However, these changes were observed at concentrations higher than the pharmacologically relevant concentration of 2 µM (Cmax). Prothrombin time and INR prolongations have been reported in patients taking vorinostat (SAHA) concomitantly with coumarin derivative anticoagulants. Monitor these patients more frequently for alterations in their coagulation parameters. Formulation: Vorinostat is supplied as a white, opaque gelatin, size 3 capsule, containing 100 mg of vorinostat. The inactive ingredients contained in each capsule are microcrystalline cellulose, sodium croscarmellose, and magnesium stearate. Vorinostat 100 mg capsules are supplied in bottles containing 120 capsules. Storage and stability: Store vorinostat capsules at room temperature, 15 to 30ºC (59 to 86ºF). Do not store above 30ºC. Avoid exposure to excessive moisture. Shelf life stability studies of the intact bottles are on-going. Administration: Oral. Unless otherwise stated in the protocol, vorinostat capsules must be administered whole. Administer doses of vorinostat with food, if possible. Special Handling: Vorinostat is an anticancer drug. Clean powder spills from broken or damaged vorinostat capsules carefully minimizing inhalation. Wash spill area at least 3 times with ethyl alcohol, followed by water. Supplier: Vorinostat is supplied by Merck and Co., Inc. and distributed by the CTEP, DCTD, NCI. Vorinostat is provided to the NCI under a Collaborative Agreement between Merck and Co., Inc. and the CTEP, DCTD, NCI (see Section 16.0).


Drug ordering: NCI-supplied agents may be requested by the Principal Investigator (or their authorized designee) at each participating institution. Pharmaceutical Management Branch (PMB) policy requires that drug be shipped directly to the institution where the patient is to be treated. PMB does not permit the transfer of agents between institutions (unless prior approval from PMB is obtained). The CTEP assigned protocol number (e.g. S0806) must be used for ordering all CTEP supplied investigational agents. The responsible investigator at each participating institution must be registered with CTEP, DCTD through an annual submission of FDA Form 1572 and a CV. If there are several participating investigators at one institution, CTEP-supplied investigational agents for the study should be ordered under the name of one lead investigator at that institution.

Drug may be requested by completing a Clinical Drug Request (NIH-986) form (http://ctep.cancer.gov/protocolDevelopment/requisition_agents/docs/clinical_drug_request.pdf) and mailing it to the Pharmaceutical Management Branch, CTEP, DCTD, NCI, 9000 Rockville Pike, EPN Rm. 7149, Bethesda, MD 20892-7422 or faxing it to 301/480-4612. For questions call 301/496-5725.

Drug Returns: All unused drug supplies should be returned to the PMB. When it is necessary to return study drug (e.g. sealed bottles remaining when expired bottles are recalled by the PMB), investigators should return the study drug to the PMB using the NCI Return Agent Form available on the CTEP home page (http://ctep.cancer.gov).

Drug Accountability: The investigator, or a responsible party designated by the investigator, must maintain a careful record of the receipt, disposition, and return of all drugs received from the PMB using the Drug Accountability Record Form available on the CTEP home page (http://ctep.cancer.gov).

Questions about drug orders, transfers, returns, or accountability should be addressed to the PMB by calling 301/496-5725 Monday through Friday between 8:30 am and 4:30 pm Eastern Time.

4.0 STAGING CRITERIA

4.1 The Ann Arbor staging criteria will be used. Stage is based on extent of disease at the time of diagnosis.

4.2 Ann Arbor Classification (AJCC Manual for Staging of Cancer, 7th ed., 2010)

STAGE II Involvement of two or more lymph node regions on the same side of the diaphragm (II) or localized involvement of an extralymphatic organ or site and its associated regional lymph nodes (IIE).

STAGE III Involvement of lymph node regions on both sides of the diaphragm (III),

which may be accompanied by localized involvement of an associated extralymphatic organ or site (IIIE) or spleen (IIIS) or both (IIISE).

STAGE IV Diffuse or disseminated involvement of one or more extra lymphatic

organs with or without associated lymph node involvement, or isolated extralymphatic organ involvement with distant (non-regional) nodal involvement).

A = Asymptomatic

B = Unexplained fever (38ºC), drenching night sweats, unexplained weight loss > 10% of

body weight over the previous six months

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4.3 "Bulky" is defined as a mediastinal mass > 1/3 of the maximum chest diameter (i.e., internal dimension of the thoracic cavity measured as its widest point per radiograph) or any other mass ≥ 10 cm in maximum diameter.

4.4 International Prognostic Index (IPI) and revised IPI (R-IPI) (22) One point is assigned for each of the following statements that is true: a. Age (over 60) b. Performance status 2-4 c. LDH greater than institutional upper limit of normal d. Extranodal disease (more than 1 site) e. Stage III or IV disease Based on the number of points assigned, the risk groups are defined as follows:

IPI Factors Risk Group R-IPI Factors Risk Group 0-1 Low 0 Very Good 2 Low-intermediate 1-2 Good 3 High-intermediate 3-5 Poor 4-5 High


5.0 ELIGIBILITY CRITERIA Each of the criteria in the following section must be met in order for a patient to be considered eligible for registration. Use the spaces provided to confirm a patient's eligibility. For each criterion requiring test results and dates, please record this information on the S0806 Prestudy Form (Form #20649) and submit to the Data Operations Center in Seattle (see Section 14.0). Any potential eligibility issues should be addressed to the Data Operations Center in Seattle at 206/652-2267 prior to registration. In calculating days of tests and measurements, the day a test or measurement is done is considered Day 0. Therefore, if a test is done on a Monday, the Monday 4 weeks later would be considered Day 28. This allows for efficient patient scheduling without exceeding the guidelines. If Day 28 or 42 falls on a weekend or holiday, the limit may be extended to the next working day.

SWOG Patient No. Patient's Initials (L, F, M) 5.1 Patients must have biopsy proven, newly diagnosed Diffuse Large B-Cell Lymphoma

(DLBCL) with Stage II bulky, Stage III or Stage IV disease, with an IPI or R-IPI score greater than 0 (see Section 4.0). A report providing confirmation of CD20 expression must be submitted per Section 14.4

5.2 Pathology review: Adequate sections from the original diagnostic specimen must be

available for submission for review by the SWOG Lymphoma Pathology Laboratory as outlined in Section 12.0. An adequate biopsy requires sufficient tissue to establish the architecture and WHO histologic subtype with certainty. Fine needle aspiration or cytology is not adequate.

5.3 Patients must be offered the opportunity to consent to the correlative science studies. Patients are encouraged to submit specimens for correlative studies as outlined in Section 15.0; however, specimen submission is not a requirement for participation in the study.

5.4 Patients must have measurable disease (see Section 10.0). Measurable disease must

be determined by CT scan of chest, abdomen and pelvis performed within 28 days prior to registration. CT reports must be submitted per Section 14.4. PET/CT may be substituted for CT scan only if CT scan is of diagnostic quality and is contrast enhanced.

5.5 Patients must be ≥ 18 years of age. 5.6 Patients must have a unilateral bone marrow aspirate and biopsy for staging performed

within 42 days prior to registration. 5.7 Patients must not have clinical evidence of central nervous system involvement by

lymphoma. Any laboratory or radiographic tests performed within 42 days prior to registration to assess CNS involvement must be negative.

5.8 Patients must not have received prior chemotherapy, radiation, or antibody therapy for

lymphoma. Steroid pre-medication for IV contrast allergy is allowed. 5.9 Patients must have Zubrod performance status of 0-2 (see Section 10.4). 5.10 Patients must have serum LDH measured within 28 days prior to registration. 5.11 Patients must have an ANC > 1,000/mcL and platelets > 100,000/mcL within 28 days

prior to registration, unless due to bone marrow infiltration by lymphoma.

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SWOG Patient No. Patient's Initials (L, F, M) 5.12 Patients must have a cardiac ejection fraction ≥ institutional lower limit of normal (ILLN)

by MUGA scan or 2-D ECHO with no significant abnormalities within 42 days prior to registration.

5.13 Patients must not have received valproic acid (a HDAC inhibitor) within 28 days prior to

registration. 5.14 Patients must have no known hypersensitivity to the components of treatment. 5.15 Patients must be willing to discontinue taking any medications that are generally

accepted to have a risk of causing Torsades de Pointes while on study (http://torsades.org).

5.16 Patients known to be HIV positive are not eligible. Existing therapeutic options are

effective and study design does not support assessing the efficacy of treatment on those with HIV.

5.17 No other prior malignancy is allowed except for the following: adequately treated basal

cell or squamous cell skin cancer, in situ cervical cancer, adequately treated Stage I or II cancer from which the patient is currently in complete remission, or any other cancer from which the patient has been disease free for five years.

5.18 Pregnant or nursing women must not participate due to potential for congenital

abnormalities, and of harm to nursing infants due to this treatment regimen. Women and men of reproductive potential must not participate unless they have agreed to use an effective contraceptive method.

5.19 All patients must be informed of the investigational nature of this study and must sign and

give written informed consent in accordance with institutional and federal guidelines. 5.20 At the time of patient registration, the treating institution's name and ID number must be

provided to the Data Operations Center in Seattle in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered into the data base.


6.0 STRATIFICATION FACTORS

Stratification factors are not applicable to this study.

7.0 TREATMENT PLAN

For treatment or dose modification questions, please contact Dr. Persky at 520/626-2218 or Dr. Miller at 520/626-8908. For dosing principles or questions, please consult the Southwest Oncology Group Policy #38 "Dosing Principles for Patients on Clinical Trials" at http://swog.org (then click on "Policies and Manuals" under the "Visitors" menu and choose Policy 38).

7.1 Good Medical Practice

The following pre-study tests/assessments are recommended within 28 days prior to registration in accordance with good medical practice. Results of these tests do not determine eligibility and minor deviations from normal limits would be acceptable if they do not affect patient safety in the clinical judgment of the treating physician. If there are significant deviations in these tests/assessments that could impact patient safety, it is highly recommended that the registering investigator discuss the patient with the Study Coordinator prior to registering. If an individual test is considered to be unnecessary, the rationale for not conducting the test must be documented in the medical record. a. Total bilirubin < 2 X IULN (unless from Gilbert’s syndrome or lymphoma). b. ALT and AST < 2 X IULN (unless from lymphoma) c. Prothrombin time (PT); Activated Partial Thromboplastin Time (aPTT) for patients

on anticoagulant therapy. This should be carefully monitored as vorinostat has been observed to prolong PT in patients on warfarin.

d. Potassium, magnesium, and calcium within normal institutional limits e. Serum creatinine ≤ 2 X IULN f. Uric acid g. Serum β2-microglobulin h. Hepatitis B virus (HBV) screening (recommended for patients at high risk of HBV

infection) i. Patients must not have an uncontrolled intercurrent illness that would exclude the

patient in the opinion of the treating physician. j. PET/CT scans: The role of PET imaging is controversial and is recommended

within 28 days prior to registration; however, it is required for restaging at treatment completion (Week 26). PET/CT scans should not replace CT scans required by the protocol, unless the CT scan of the PET/CT hybrid is contrast-enhanced and of diagnostic quality.

k. Patients must not have a current condition, treatment, or lab abnormality that

might confound the results of the study in the opinion of the treating physician, including procedures that might interfere with the absorption or swallowing of the study drugs. They must have recovered from any recent conditions, treatments, or surgeries.

S0806 Page 27 Revised 12/23/10 Revised 8/26/11

7.2 Treatment Overview

The study will be conducted in two sequential parts. A patient may be enrolled to either the Phase I portion or the Phase II portion, but not both. Phase I – In the Phase I portion of the study, patients will be treated with vorinostat and R-CHOP to determine the optimal dose of vorinostat (SAHA). Details are in Section 7.4. Phase II – In the Phase II portion of the study, patients will receive R-CHOP in combination with the vorinostat at the dose determined in the Phase I portion of the study. Details are in Section 7.5.

7.3 Pre-Medication – applicable to both the Phase I and Phase II portions of the study

a. Tumor lysis prophylaxis is recommended for patients with high tumor burden. b. Use of growth factors (such as G-CSF, GM-CSF, or Pegylated G-CSF) and of

erythropoiesis stimulating agents (such as erythropoietin or darbopoietin) is allowed, per ASCO guidelines (http://jop.ascopubs.org/cgi/content/full/2/4/196).

c. Use of anti-diarrheal agents such as loperamide is at the discretion of the treating physician.

d. Premedication for rituximab is mandatory and is per institutional guidelines. e. Use of prophylactic antibiotics to prevent febrile neutropenia is at the discretion of

the treating physician. 7.4 Phase I Treatment

Agent Dose Route Day Schedulea

Vorinostat b* Dose level assigned

PO

Days assigned

Every 21 days for 8 cycles

Rituximab c,d 375 mg/m2 IV infusion Day 3 Every 21 days for 8 cycles

Cyclophosphamide d 750 mg/m2 IV infusion over 30-60

minutes Day 3 Every 21 days for 8

cycles

Doxorubicin d 50 mg/m2 IV push Day 3 Every 21 days for 8 cycles

Vincristine d 1.4 mg/m2

(max 2 mg) IV push Day 3 Every 21 days for 8

cycles

Prednisone d 100 mg PO once daily Days 3-7 Every 21 days for 8

cycles a One cycle = 21 days b The level will be assigned at the time of registration and communicated to the registering institution as part

of the registration confirmation per Section 7.4a.5. and the dose level chart in Section7.4a.1. Vorinostat should be administered as a whole capsule with food, if possible

c If the circulating lymphocyte count (i.e. leukemic cells) is > 5,000 cells/mcL at the start of R-CHOP administration (Day 3), rituximab administration may be modified or omitted per discretion of the treating physician in order to prevent the risk of tumor lysis and cytokine release syndrome. Modifications/omissions must be recorded in the S0806 Treatment Form (Form #8053).

d Rituximab will be followed immediately by CHOP. If both rituximab and CHOP cannot fit in one day, CHOP can be given on Day 4.

* Use of growth factors is recommended after vorinostat dosing is completed. IMPORTANT NOTE: The Phase I portion of this trial requires rapid reporting of dose limiting toxicities. See Section 15.1 for details.


a. Dose Determination Rules

1. There will be three vorinostat dose levels:

Dose level 0 400 mg PO Once daily Days 1-9 Dose level -1 300 mg PO Once daily Days 1-9 Dose level -2 300 mg PO Once daily Days 1-5

2. Dose-Limiting Toxicity (DLT) is defined in Section 7.4b.

3. Only DLTs occurring during the first 3 calendar weeks (Cycle 1) will be

used to guide dosing of vorinostat.

4. Patients will be considered evaluable for DLT if they are eligible, and if they receive any amount of treatment and experience DLT or complete the first cycle of treatment. Patients who are not evaluable will be replaced.

5. The following dosing scheme will be used for dose determination:

Evaluate 10 patients at Dose Level 0 (400 mg PO daily, Days 1-9):

• If 3/10 or fewer patients have DLT at Dose Level 0, this will be the dose for the Phase II trial.

• If more than 3/10 patients have DLT at Dose Level 0, stop enrollment

at this dose after the 4th patient develops DLT and enroll 10 patients at Dose Level -1 (300 mg PO daily, Days 1-9).

• If 3/10 or fewer patients have DLT at Dose Level -1, this will be the

dose for the Phase II trial.

• If more than 3/10 patients have DLT at Dose Level -1, stop enrollment at this dose after the 4th patient develops DLT and enroll 10 patients at Dose Level -2 (300 mg PO, daily, Days 1-5).

• If 3/10 or fewer patients have DLT at Dose Level -2, this will be the

dose for the Phase II trial.

• If more than 3/10 patients have DLT at Dose Level -2, stop enrollment after the 4th patient develops DLT.

b. Definition of Dose-Limiting Toxicity (DLT)

See Section 8.1 for information regarding the NCI Common Terminology Criteria for Adverse Events (CTCAE). DLTs apply only during Cycle 1 and should be drug-related (possible, probable, or definite). The following events occurring in the first cycle of treatment are considered dose-limiting:

1. Non-Blood/Bone Marrow toxicity that persists despite adequate

treatment: development of any Grade 3 or greater non-blood/bone marrow toxicity which persists until Day 1 of Cycle 2 despite adequate treatment.


Clarifications: a. Grade 3 or 4 allergic reactions or skin changes within 48 hours

following rituximab administration will NOT be a DLT. b. Grade 3 or 4 nausea, vomiting, or diarrhea WILL be a DLT - if it

persists despite appropriate anti-emetic and anti-diarrheal therapy.

c. Grade 3 or 4 hyperglycemia WILL be a DLT - if symptomatic or

glucose level of > 300 mg/ml persists despite appropriate management (including administration of insulin and/or diabetic agents).

d. Grade 3 or 4 hypokalemia, hypophosphatemia, or

hypomagnesemia WILL be a DLT – if it persists despite appropriate repletion.

e. Grade 3 or 4 febrile neutropenia and hemorrhage WILL always

be a DLT.

2. Blood/Bone Marrow toxicity:

a. Grade 3-4 neutrophil count decrease lasting more than 7 days. ANC must be > 1,000 cells/mcL before receiving R-CHOP.

b. Grade 3-4 platelet count decrease lasting more than 7 days.

Platelet count must be > 100,000 cells/mcL before receiving R-CHOP. • Grade 3-4 platelet count decrease associated with at least

Grade 2 hemorrhage WILL be a DLT regardless of platelet count decrease duration.

3. Delay of treatment with ANY agent for 7 days or more due to possibly,

probably, or definitely treatment related toxicity during Cycle 1.

c. Except when they conflict with Section 7.4, the guidelines included in Section 8.0 should be followed for patients on the Phase I portion of the study.

d. A patient on the Phase I portion of the study who develops a DLT while on Dose

Level 0 should have treatment held until the toxicity resolves, and then may continue on treatment at Dose Level -1. A patient on the Phase I portion of the study who develops a DLT while on Dose Level -1 should have treatment held until the toxicity resolves (generally to Grades 0-1 except as noted in Section 7.4b and 8.0), and then may continue on treatment at Dose Level -2. A patient on Dose Level -2 who develops a DLT will have treatment stopped, will not receive further vorinostat and will be removed from protocol treatment (see Section 8.2c). Only DLTs occurring in the first three calendar weeks (Cycle 1) and at the patient’s first dose level of treatment will be used to guide dose determination for the Phase II portion of the trial as per Section 7.4a.

e. A temporary closure will occur prior to opening this study for the Phase II portion

in order to assess dose and to evaluate the safety profile more fully prior to implementation of the Phase II trial. This evaluation will be conducted by the Study Coordinator, Disease Committee Chair, Adverse Event Coordinator, and Study Statistician in conjunction with NCI staff. Frequency of reporting in the Phase II portion of the trial may be modified depending upon patterns observed in the Phase I portion.


7.5 Phase II Treatment

The Phase II portion of the trial will be initiated Group-wide. Vorinostat will be administered daily orally with food at the dose and duration determined during the Phase I part of the study. R-CHOP will be administered on Day 3. Therapy will continue for 8 cycles, with a cycle being defined as 21-day course of vorinostat-R-CHOP or 3 weeks of treatment. All patients that started vorinostat will be considered evaluable. Restaging will be performed before Cycle 5 and patients showing progression will be removed from protocol treatment.

Agent Dose Route Day Schedulea

Vorinostat b 400 mg PO

Days 1-9 Every 21 days for

8 cycles

Rituximab c,d 375 mg/m2 IV infusion Day 3 Every 21 days for 8 cycles

Cyclophosphamide c 750 mg/m2 IV infusion over 30-60

minutes Day 3 Every 21 days for

8 cycles

Doxorubicin c 50 mg/m2 IV push Day 3 Every 21 days for 8 cycles

Vincristine c 1.4 mg/m2

(max 2 mg) IV Push

Day 3 Every 21 days for 8 cycles

Prednisone c 100 mg PO

once daily Days 3-7 Every 21 days for

8 cycles a One cycle = 21 days b Vorinostat should be administered as whole capsule with food, if possible. c Rituximab will be followed immediately by CHOP. If both rituximab and CHOP cannot fit in one day,

CHOP can be given on Day 4. d If the circulating lymphocyte count (i.e. leukemic cells) is > 5,000 cells/mcL at the start of R-CHOP

administration (Day 3), rituximab administration may be modified or omitted per discretion of the treating physician in order to prevent the risk of tumor lysis and cytokine release syndrome. Modifications/omissions must be recorded in the S0806 Treatment Form (Form #61095).

7.6 Drug compliance will be recorded by patients in the Intake Calendar (see Appendix 19.2).

Institutional CRAs will review and ascertain patient adherence with protocol therapy at the end of treatment for each cycle. Calendar should be kept in the patient's clinic chart. Note that the Intake Calendar is provided only as a tool for tracking patient compliance. Site may utilize institutional pill diaries or other source documentation in place of the Intake Calendar at the discretion of the treating physician.

7.7 Because this study contains an investigational drug for which CTEP holds the IND, it falls

under CTEP requirements for full reporting. This involves required submission of cycle-specific toxicity and dose information (see Section 14.8 and the S0806 Treatment and Adverse Event Forms (Form #8053, #12947).

7.8 Criteria for Removal from Protocol Treatment

a. Progression of disease (as defined in Section 10.2d).

b. Development of unacceptable toxicity, as defined in Section 8.0.

c. Delay of protocol treatment for more than two weeks from date of scheduled

administration.

d. Completion of protocol treatment.

e. The patient may withdraw from the study at any time for any reason.


7.9 All reasons for discontinuation of treatment must be documented in the Off Treatment Notice (Form #52393).

7.10 All patients will be followed for 5 years after registration or until death, whichever occurs

first. 8.0 TOXICITIES TO BE MONITORED AND DOSAGE MODIFICATIONS

8.1 This study will utilize the CTCAE (NCI Common Terminology Criteria for Adverse Events) Version 4.0 for toxicity and Serious Adverse Event reporting. A copy of the CTCAE Version 4.0 can be downloaded from the CTEP home page (http://ctep.cancer.gov). All appropriate treatment areas should have access to a copy of the CTCAE Version 4.0.

8.2 General Considerations

a. Sections 8.3-8.6 apply to both the Phase I and Phase II portions of the study. However, if these conflict with Sections 7.4b-7.4d for a patient on the Phase I portion, then Sections 7.4b-7.4d take precedence.

b. Dose reductions of a drug should be done only for toxicities that are related to

the agent, are clinically significant, and cannot be managed by supportive care.

c. If any drug is permanently stopped for toxicity the patient will be taken off protocol treatment.

8.3 Dose Modifications of Vorinostat

a. During continuous treatment with vorinostat, it may be necessary to hold

treatment for toxicities > Grade 2 that develop while the patient is receiving drug. If multiple toxicities are experienced, dose modification will be based on the toxicity requiring the largest dose reduction.

b. No dose escalations or dose re-escalations of vorinostat are permitted.

c. Missed days of vorinostat will not be made up. The indications to interrupt

continuous therapy are outlined below. Any dose adjustments must be clearly outlined in the S0806 Treatment Form (Form #8053). Dosage adjustments for future cycles should be made according to this table. AGENT DOSE LEVEL DOSE DAYS Vorinostat 0 400 mg 1-9

-1 300 mg 1-9 -2 300 mg 1-5

d. Dose Reduction Schedule for Blood/Bone Marrow Toxicities

Platelet Count Decrease

Toxicity Treatment guidelines

Grade 1-2 No dose reduction. Use appropriate supportive measures.

Grade 3-4 1st and 2nd episodes: discontinue vorinostat for that cycle

and hold R-CHOP until recovery to ≥ 100,000/mcL. For the following cycle, decrease vorinostat by 1 dose level.

3rd episode: Discontinue protocol treatment.

S0806 Page 32

Neutrophil Count Decrease Toxicity Treatment guidelines Grade 1-2 No dose reduction. Use appropriate supportive

measures. Grade 3-4 1st and 2nd episodes: Discontinue vorinostat for that

cycle and hold R-CHOP until recovery to Grade 0-2; apply appropriate supportive measures such as growth factors. For the following cycle, decrease vorinostat by one dose level.

3rd episode: Discontinue vorinostat for that cycle and

hold R-CHOP until recovery to Grade 0-2; apply appropriate supportive measures such as growth factors. If after a 1-week delay ANC does not recover to Grade 0-2, decrease cyclophosphamide and doxorubicin doses by 25%.

4th episode: Discontinue protocol treatment.

Anemia Toxicity Treatment guidelines Grade 1-3 No dose reduction. Use appropriate supportive

measures.

Grade 4 1st and 2nd episodes: discontinue vorinostat for that cycle and hold R-CHOP until recovery to Grade 0-1, use appropriate supportive measures, decrease vorinostat by one dose level.

3rd episode: Discontinue protocol treatment.

e. Management of treatment-emergent Grade 3 and 4 Electrocardiogram QT

corrected interval prolonged: Grade 3 (1st and 2nd episodes): Discontinue vorinostat for the remainder of the cycle until resolved to Grade 0-2, then reduce vorinostat by one dose level for the next cycle. Grade 3 (3rd episode) or Grade 4: Discontinue protocol treatment.

f. Vorinostat was observed to prolong PT in patients on warfarin. Therefore,

Prothrombin time (PT) or Activated Partial Thromboplastin Time (aPTT) should be monitored for patients on anticoagulant therapy and the dose of anticoagulant should be modified as needed.

g. Other non-Blood/Bone Marrow toxicity that is believed to be due to vorinostat:

Grades 3-4 (1st and 2nd episodes): Discontinue vorinostat for the remainder of the cycle and hold R-CHOP for up to 2 weeks until resolved to Grade 0-1, then reduce vorinostat by one dose level for the next cycle. If toxicity does not resolve to Grade 0-1 within 2 weeks, discontinue protocol treatment. Grades 3-4 (3rd episode): Discontinue protocol treatment.

S0806 Page 33

8.4 CHOP Dose Modification:

a. Blood/Bone Marrow Toxicities: The R-CHOP regimen should be given as described in Section 7.0 if the ANC is > 1,000 cells/mcL and the platelets are > 100,000 cells/mcL by the time the next cycle is due. Re-escalation is at the discretion of the treating physician. Cytokines may be administered to prevent neutrophil count decrease. The NCI will not provide cytokines for this study.

b. Impaired Hepatic Function: All patients with bilirubin ≤ 2 x the institutional upper

limit of normal will receive a full initial dose of doxorubicin and vincristine. If the bilirubin rises to > 2 x the institutional upper limit of normal (but ≤ 5 x IULN), the doxorubicin and vincristine doses must be reduced by 50% of last dose received to avoid undue hepatic toxicity. Full doses should be given once the bilirubin is ≤ 2 x the institutional upper limit of normal. If the bilirubin rises to > 5 x the institutional upper limits of normal, doxorubicin and vincristine should be discontinued for that cycle. If hepatic function has not recovered to ≤ 2 x the institutional upper limits of normal by the time the next cycle is due, then remove patient from protocol treatment. In cases of obstruction of biliary duct by tumor mass, a biliary drainage shunt should be placed prior to chemotherapy.

Bilirubin Doxorubicin Dose Vincristine Dose

≤ 2 x IULN 100% 100%

> 2 - 5 x IULN 50% (of last 50% (of last dose received) dose received) > 5 x IULN Discontinue Discontinue

c. Impaired Renal Function: All patients with serum creatinine levels ≤ 2 x the

institutional upper limit of normal will receive full dose of all drugs. If creatinine rises to > 2 x the institutional upper limit of normal, the dose of cyclophosphamide must be reduced by 25% from last dose. Re-escalation is at the discretion of the treating physician if the serum creatinine level drops to ≤ 2 x the institutional upper limit of normal.

d. Cystitis Noninfective: Cyclophosphamide will be discontinued and the patient

removed from protocol treatment if Grade 3 or 4 hemorrhagic cystitis resulting from this drug occurs. Adequate fluid intake is recommended during therapy.

e. Peripheral Motor Neuropathy: Patients experiencing Grade 3 vincristine-related

neuropathy (e.g., obstipation, weakness) will have the dose of vincristine reduced by 50% for all further cycles of CHOP. Patients experiencing Grade 4 vincristine- related neuropathy will have vincristine omitted from all future cycles of CHOP.

8.5 Rituximab Dose Modification:

a. Patients may experience transient fever and chills with infusion of rituximab. If

Grade 2 chills (or Grade 2 fever with chills) are noted, the antibody infusion should be temporarily discontinued, the patient should be observed, and the severity of the side effects should be evaluated. The patient should be treated according to the best available local practices and procedures. Following observation, when fever resolves to Grade 2 or less and chills to Grade 1 or less, the infusion should be continued, initially, at half the previous rate. Following the antibody infusion, the IV line should be kept open for medications, as needed.

S0806 Page 34

b. Hypotension, bronchospasm and angioedema have occurred as part of an infusion related symptom complex. If a Grade 3 or greater allergic reaction occurs, antibody infusion should be interrupted and may be resumed at a 50% reduction in rate when symptoms have completely resolved. Treatment with diphenhydramine and acetaminophen is recommended; additional treatment with bronchodilators or IV saline may be used at the physician's discretion.

c. Precautionary hospitalization for patients experiencing severe infusion

symptoms, which do not resolve after discontinuation of the cycle, is recommended. If there are no complications, the IV line may be discontinued after one hour of observation. If complications occur during the rituximab infusion, the patient should be observed for two hours after the completion of the infusion. If a patient experiences a Grade 3 toxicity that persists until the next scheduled infusion, the patient must discontinue treatment until toxicities have resolved to Grade 2 or less. If treatment is delayed for more than two weeks, remove the patient from protocol treatment.

d. Tumor Lysis Syndrome: Appropriate medical therapy should be provided for

patients who develop tumor lysis syndrome. Following treatment for and resolution of tumor lysis syndrome, subsequent rituximab therapy may be administered in conjunction with prophylactic therapy for this syndrome. Contact the Study Coordinator prior to resuming treatment in these patients.

e. Hepatitis B Reactivation with Related Fulminant Hepatitis and Other Viral

Infections: Carriers of hepatitis B should be closely monitored for clinical and laboratory signs of active HBV infection and for signs of hepatitis throughout their study participation. Patients with any evidence of active hepatic disease or known HBV infection should be managed as clinically appropriate and should only receive rituximab if they have control of the infection and are adequately informed of the risks. Patients who have never received vaccination for HBV, and have not had serologic testing for HBsAg, should be tested for surface antigen positivity.

In patients who develop progressive multifocal leukoencephalopathy (PML), rituximab should be discontinued and reductions or discontinuation of concomitant immunosuppressive therapy and appropriate treatment, including antiviral therapy, should be considered. Physicians should consider PML in any patients presenting with new onset neurologic manifestations, particularly in patients with systemic lupus erythematosus (SLE) or lymphoid malignancies. Consultation with a neurologist, brain MRI, and lumbar puncture should be considered as clinically indicated. There are no known interventions that can reliably prevent PML or adequately treat PML if it occurs.

f. Severe Mucocutaneous Reactions: All patients on and off rituximab therapy

should be closely monitored for signs and symptoms suggestive of severe cutaneous and mucocutaneous reactions. Should these symptoms arise, discontinue rituximab therapy (if applicable) and support as clinically indicated.

g. Cardiovascular events: Patients with rheumatoid arthritis (RA) are at increased

risk for cardiovascular events compared to the general population. Patients with RA should be monitored throughout the infusion, and rituximab should be discontinued in the event of a serious or life-threatening cardiac event. Patients who develop clinically significant arrhythmias should undergo cardiac monitoring during and after subsequent infusions of rituximab. Patients with pre-existing cardiac conditions, including arrhythmias and angina, that have had recurrences of these events during rituximab therapy should be monitored

S0806 Page 35

throughout the infusion and immediate post-infusion period. Patients off rituximab therapy should be closely monitored for signs and symptoms suggestive of life-threatening cardiac events and supported as clinically indicated.

h. Bowel obstruction and perforation: Complaints of abdominal pain, especially

early in the course, should prompt a thorough diagnostic evaluation and appropriate treatment. If patient experiences a bowel obstruction or perforation, discontinue rituximab therapy. Patients off rituximab therapy should be closely monitored for signs and symptoms suggestive of bowel obstruction and supported as clinically indicated.

i. Renal: Discontinuation of rituximab should be considered for those with rising

serum creatinine or oliguria.

8.6 Supportive Care Guidelines for Vorinostat

a. Diarrhea: Diarrhea should be treated promptly with appropriate supportive care, including loperamide. Loperamide should not be taken prophylactically. Patients should be instructed to begin taking loperamide at the first sign of: 1) poorly formed or loose stool, 2) occurrence of more bowel movements than usual in one day or 3) unusually high volume of stool. Loperamide should be taken in the following manner: 4 mg at first onset of diarrhea, then 2 mg after each unformed stool. The daily dose of loperamide should not exceed 16 mg/day. Loperamide should be deferred if blood or mucus is present in the stool or if diarrhea is accompanied by fever. In this setting, appropriate diagnostic microbiologic specimens should be obtained to exclude an infectious etiology. Patients should also be advised to drink liberal quantities of clear fluids, at least 2 liters daily on Days 1-9, to help prevent dehydration.

b. Nausea/vomiting: Nausea and vomiting should be treated aggressively, and

strong consideration should be given to the administration of prophylactic antiemetic therapy according to standard institutional practice. In particular, the use of antiemetics including 5HT3 antagonists and/or aprepitant plus dexamethasone is encouraged. Patients should be strongly encouraged to maintain liberal oral fluid intake (at least 2 liters daily) during therapy, especially during the initial 9 days of each treatment cycle.

c. Anemia: Treatment with vorinostat can cause dose-related anemia. If

appropriate, the dose of vorinostat may be modified or therapy discontinued. (See Section 8.3 for dose modification guidelines.) Transfusions [and/or erythropoietin] may be utilized as clinically indicated for the treatment of anemia, but should be clearly noted as concurrent medications.

d. Platelet Count Decrease: Treatment with vorinostat can cause dose-related

platelet count decrease. If platelet counts are reduced during treatment with vorinostat, the vorinostat dose may be modified or therapy discontinued. Transfusion of platelets may be used if clinically indicated in a manner consistent with the guidelines for dose modification (see Section 8.3).

e. Neutrophil Count Decrease: G-CSF, pegylated G-CSF, or GM-CSF may be

utilized per ASCO guidelines (http://jop.ascopubs.org/cgi/content/full/2/4/196). f. Hyperglycemia: Hyperglycemia has been observed in patients receiving

vorinostat. Serum glucose should be monitored. Adjustment of diet and/or anti-hyperglycemic therapy may be necessary.


g. Hypokalemia/hypomagnesemia: Levels should be corrected prior to administration of vorinostat, and consideration should be given to monitoring potassium and magnesium in symptomatic patients (e.g. patients with nausea, vomiting, diarrhea, fluid imbalance or cardiac symptoms.)

h. Pulmonary embolism and thromboembolic events: Pulmonary embolism and

deep vein thrombosis have been reported. Investigators should be alert to the signs and symptoms of these events. Physicians should be alert to the signs and symptoms of these events, particularly in patients with a prior history of thromboembolic events.

i. Cardiac events: Electrocardiogram QT corrected interval prolongation has been

observed. Baseline and periodic EKGs must be performed during treatment (see Sections 9.1 and 9.2). Vorinostat should be administered with particular caution in patients with congenital long QT syndrome and patients taking anti-arrhythmic medicines or other medicinal products that lead to electrocardiogram QT corrected interval prolongation. Please refer to the website (http://www.azcert.org) for the list of such medicines or medicinal products.

8.7 For treatment or dose modification questions, please contact Dr. Persky at 520/626-2218

or Dr. Miller at 520/626-8908. 8.8 Toxicities (including suspected reactions) that meet the expedited reporting criteria as

outlined in section 16.0 of the protocol must be reported to the Operations Office, Study Coordinator and NCI via AdEERS, and to the IRB per local IRB requirements.

9.1 STUDY CALENDAR - Phase I S0806, "A Phase I/II Trial of Vorinostat (SAHA) (NSC-701852) in Combination With Rituximab-CHOP in Patients With Newly Diagnosed Advanced Stage Diffuse Large B-Cell Lymphoma (DLBCL)"

√ √

RestagingPre-

progressionPost-

progressionREQUIRED STUDIES Wk Wk Wk Wk Wk Wk Wk Wk Wk Wk Wk Wk Wk Wk Wk Wk Wk Wk Wk Wk Wk Wk Wk Wk Wk

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 26PHYSICAL

History and Physical Exam X X X X X X X X X X XWeight and Performance Status X X X X X X X X X X XBaseline Abnormalities Assessment XDisease Assessment X X X XToxicity Notation X X X X X X X X X X X X X X X X X X X X X X X X XIntake Calendar □ X X X X X X X X

LABORATORYCBC/Differential/Platelets* X X X X X X X X XSerum creatinine, Potassium, Calcium,Magnesium X** X X X X X X X XBilirubin, total X** X X X X X X X XALT and AST X** X X X X X X XUric acid X**Serum Beta-2 microglobulin X** XPT/INR or aPTT# X**HBV screening ∆ X**nmm X X XBone marrow asp/biopsy XMaterials for pathology review X

X-RAYS AND SCANSCT chest/abdomen/pelvis £ X X X XPET/CT X** XMUGA or 2-d ECHO XEKG (see Section 8.6i) X¥ X X X

RESEARCH SPECIMENS (See Section 15.0)Paraffin Block XCore needle biopsy (optional) XWhole Blood and Serum X X

TREATMENT (See Section 7.4)Vorinostat † X X X X X X X X X X X X X X X XRituximab (Day 3) X X X X X X X XCyclophosphamide (Day 3) X X X X X X X XDoxorubicin (Day 3) X X X X X X X XVincristine (Day 3) X X X X X X X XPrednisone (Days 3-7) X X X X X X X XNote: All forms utilized for this study are listed in Section 18.0. Forms submission guidelines are found in Section 14.0.

* Patients may be evaluated on Day 1 or Day 3 of Cycles 2-8, as long as a CBC and electrolytes are obtained on Day 1 prior to vorinostat initiation.** Results of these tests do not determine eligibility but are recommended prior to registration in accordance with Good Medical Practice (see Section 7.1).# Perform in patients on anticoagulants (to be monitored as needed). ∆ Recommended for patients at high risk of HBV infection.† The vorinostat dose level will be assigned at the time of registration and communicated to the registering institution as part of the registration confirmation. Dose Level 0 = 400 mg PO daily, Days 1-9. Dose Level -1 = 300 mg PO daily, Days 1-9. Dose Level -2 = 300 mg PO daily, Days 1-5.√ Patients removed from protocol treatment for any reason will be evaluated at that time by repeating CBC with platelets, LDH, CT of chest, abdomen and pelvis, and all pre-treatment scans to evaluate disease. Follow-up evaluations will occur every six months for two years then annually for a maximum of five years on protocol. □ CRA will review Intake Calendar at each visit (see Appendix 19.2).£ PET/CT may be substituted for CT scan only if CT scan is of diagnostic quality and is contrast enhanced (see Section 5.4).¥ The baseline EKG can be completed anytime between 28 days prior to registration and Cycle 1 Day 1 treatment.

Cycle 4Cycle 1FOLLOW

UP

Cycle 2 Cycle 3PRE

STUDY

Cycle 8FOLLOW

UP

Cycle 7Cycle 5 Cycle 6

S0806Page 37

Revised 12/23/10Revised 3/23/11Revised 8/26/11

9.2 STUDY CALENDAR - Phase II S0806, "A Phase I/II Trial of Vorinostat (SAHA) (NSC-701852) in Combination With Rituximab-CHOP in Patients With Newly Diagnosed Advanced Stage Diffuse Large B-Cell Lymphoma (DLBCL)"

√ √

RestagingPre-

progressionPost-

progressionREQUIRED STUDIES Wk Wk Wk Wk Wk Wk Wk Wk Wk Wk Wk Wk Wk Wk Wk Wk Wk Wk Wk Wk Wk Wk Wk Wk Wk

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 26PHYSICAL

History and Physical Exam X X X X X X X X X X XWeight and Performance Status X X X X X X X X X X XBaseline Abnormalities Assessment XDisease Assessment X X X XToxicity Notation X X X X X X X XIntake Calendar □ X X X X X X X X

LABORATORYCBC/Differential/Platelets* X X X X X X X X XSerum creatinine, Potassium, Calcium,Magnesium X** X X X X X X X XBilirubin, total X** X X X X X X X XALT and AST X** X X X X X X XUric acid X**Serum Beta-2 microglobulin X** XPT/INR or aPTT # X**HBV screening ∆ X**LDH X X XBone marrow asp/biopsy XMaterials for pathology review X

X-RAYS AND SCANSCT chest/abdomen/pelvis £ X X X XPET/CT X** XMUGA or 2-d ECHO XEKG (see Section 8.6i) X¥ X X X

RESEARCH SPECIMENS (See Section 15.0)Paraffin Block XCore needle biopsy (optional) XWhole Blood and Serum X X

TREATMENT (See Section 7.45Vorinostat † X X X X X X X X X X X X X X X XRituximab (Day 3) X X X X X X X XCyclophosphamide (Day 3) X X X X X X X XDoxorubicin (Day 3) X X X X X X X XVincristine (Day 3) X X X X X X X XPrednisone (Days 3-7) X X X X X X X XNote: All forms utilized for this study are listed in Section 18.0. Forms submission guidelines are found in Section 14.0.

* Patients may be evaluated on Day 1 or Day 3 of Cycles 2-8, as long as a CBC and electrolytes are obtained on Day 1 prior to vorinostat initiation.** Results of these tests do not determine eligibility but are recommended prior to registration in accordance with Good Medical Practice (see Section 7.1).# Perform in patients on anticoagulants (to be monitored as needed). ∆ Recommended for patients at high risk of HBV infection.† The vorinostat dose level and schedule will be determined after the Phase I is completed.√ Patients removed from protocol treatment for any reason will be evaluated at that time by repeating CBC with platelets, LDH, CT of chest, abdomen and pelvis, and all pre-treatment scans to evaluate disease. Follow-up evaluations will occur every six months for two years then annually for a maximum of five years on protocol. □ CRA will review Intake Calendar at each visit (see Appendix 19.2).£ PET/CT may be substituted for CT scan only if CT scan is of diagnostic quality and is contrast enhanced (see Section 5.4).¥ The baseline EKG can be completed anytime between 28 days prior to registration and Cycle 1 Day 1 treatment.

PRE STUDY

Cycle 8FOLLOW

UP

Cycle 7Cycle 5 Cycle 6Cycle 4Cycle 1FOLLOW

UP

Cycle 2 Cycle 3

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Revised 3/23/11Revised 8/26/11

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10.0 CRITERIA FOR EVALUATION AND ENDPOINT DEFINITIONS 10.1 Measurability of Lesions:

a. Measurable Disease: Lesions that can be accurately measured in two dimensions by CT, MRI, plain x-ray, or other conventional technique and have a greatest transverse diameter of 1 cm or greater; or palpable lesions with both diameters 2 cm or greater. Note: PET scans are insufficient for evaluation of measurable disease.

b. Non-measurable Disease: All other lesions including unidimensional lesions,

lesions too small to be considered measurable, pleural or pericardial effusion, ascites, bone disease, leptomeningeal disease, lymphangitis, pulmonitis, abdominal masses not confirmed or followed by CT or disease documented only by PET imaging or indirect evidence (e.g., lab values).

10.2 Objective Disease Status: Objective status is to be recorded at each evaluation

according to the 2007 revised Cheson et al. criteria. (26) All measurable lesions up to a maximum of 6 lesions (largest) should be identified as target lesions at baseline. If there are more than 6 measurable lesions the remaining will be identified as non-target lesions and included as non-measurable disease. The 6 lesions should be selected according to the following features: they should be from as disparate regions of the body as possible and they should include mediastinal and retroperitoneal areas of disease if these sites have measurable lesions. Measurements must be provided for target lesions, while presence or absence must be noted for non-target measurable and non-measurable disease.

a. Complete Response (CR): Complete disappearance of all measurable and

non-measurable disease with the exception of the following. In patients with no pretreatment PET scan or when the PET scan was positive before therapy, a post-treatment residual mass of any size is permitted as long as it is PET negative. If the PET scan was negative before therapy, all nodal masses > 1.5 cm in greatest transverse diameter (GTD) at baseline must have regressed to ≤ 1.5 cm in GTD and all nodal masses > 1 cm and ≤ 1.5 cm in GTD and > 1 cm in their short axis before treatment must have regressed to ≤ 1 cm in their short axis. No new lesions visible on PET scan or by any other imaging studies. The spleen and/or liver, if considered enlarged at baseline based on physical examination or imaging study (other than PET), must have regressed in size and must not be palpable. If bone marrow was positive at baseline, it must be negative based on biopsy and aspirate at same site. Normalization of markers (e.g., LDH definitely assignable to NHL). Tumor measurements must be obtained by an imaging modality other than PET. All disease must be assessed using the same technique as baseline.

b. Partial Response (PR): Applies to patients with at least one lesion that does not

qualify for a CR. For patients with measurable disease, ≥ 50% decrease in sum of the product of the diameters (SPD) of up to six dominant lesions identified at baseline. No new lesions and no increase in the size of the liver, spleen, or other nodes. Splenic and hepatic nodules must have regressed by ≥ 50% in SPD. In patients with no pretreatment PET scan or when the PET scan was positive before therapy, PET should be positive in at least one previously involved site. Tumor measurements must be obtained by an imaging modality other than PET. All disease must be assessed using the same technique as baseline. Note: Patients who meet all other criteria, but have new lesions observed on PET scan only (i.e., not confirmed on CT or other imaging studies), are considered partial responders.

c. Stable Disease (SD): Does not qualify for CR, PR, or Relapsed/Progressive

Disease. Tumor measurements must be obtained by an imaging modality other than PET. All disease must be assessed using the same technique as baseline.

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d. Relapsed Disease (after CR)/Progressive Disease (after PR, SD): At least 50% increase in the SPD of target measurable nodal lesions over the smallest sum observed (over baseline if no decrease during therapy), or ≥ 50% increase in the GTD of any node > 1 cm in shortest axis, or ≥ 50% increase in the SPD of other target measurable lesions (e.g., splenic or hepatic nodules) over the smallest sum observed. Appearance of any new bone marrow involvement. Appearance of any new lesion > 1.5 cm in longest axis, or ≥ 50% increase in GTD of any previously involved node with a diameter ≤ 1.0 cm in the short axis such that its longest axis is now > 1.5 cm. Lymph nodes should be considered abnormal for relapse or progressive disease only if the long axis is > 1.5 cm, or if the both the long and short axes are > 1 cm. In patients with no pretreatment PET scan or when the PET scan was positive before therapy, lesions should be PET positive. Tumor measurements must be obtained by an imaging modality other than PET. All disease must be assessed using the same technique as baseline. Note: Appearance of any new lesion on PET alone (not confirmed by CT or other imaging modality) is NOT considered relapse/progression.

10.3 Best Response:

a. CR: One objective status of CR documented before relapse. b. PR: One objective status of PR documented before progression but not

qualifying as a CR. c. Stable: At least one objective status of stable documented at least 6 weeks after

registration, not qualifying as anything else above. e. Increasing Disease: Objective status of progression within 12 weeks of

registration not qualifying as anything else above. e. Inadequate assessment, response unknown: Progression greater than 12 weeks

after registration and no other response category applies. 10.4 Performance Status: Patients will be graded according to the Zubrod performance

status scale:

GRADE SCALE 0 Fully active; able to carry on all pre-disease activities without

restriction.

1 Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light housework, office work.

2 Ambulatory and capable of all self-care but unable to carry out

any work activities; up and about more than 50% of waking hours.

3 Capable of only limited self-care; confined to bed or chair more

than 50% of waking hours.

4 Completely disabled; cannot carry on any self-care; totally confined to bed or chair.

10.5 Progression-Free Survival: From date of registration to date of first observation of

progressive disease (as defined in Section 10.2d), or death due to any cause. Patients last known to be alive and without report of progression are censored at date of last contact.

10.6 Time to Death: From date of registration to date of death due to any cause. Patients

last known to be alive are censored at date of last contact.

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11.0 STATISTICAL CONSIDERATIONS

11.1 This study will initially be in limited institutions, with expected accrual of 10-30 patients in the Phase I portion of the trial. The Phase II portion of the trial will be initiated Group-wide. Based on previous experience in this disease, we anticipate accrual of 4 patients per month.

11.2 Phase I study: Patients will receive vorinostat with standard R-CHOP as described in

Section 7.4. Initially, patients will be treated at a vorinostat dose of 400 mg PO daily, Days 1-9. If this dose is not well-tolerated, then 300 mg PO daily, Days 1-9 and (if necessary) 300 mg PO daily, Days 1-5 will be explored. Ten patients will be evaluated at the recommended dose prior to proceeding with the Phase II portion of the trial.

11.3 The Phase I portion of this trial will include intensive monitoring of adverse events in a

minimum of 10 patients. A temporary closure will occur prior to opening this study for the Phase II portion in order to assess dose, and to evaluate the safety profile more fully. Assuming this trial opens to the Phase II portion, adverse event reporting will continue to be monitored on a regular basis. Frequency of reporting may be modified depending upon patterns observed in the Phase I portion of the trial. See Section 15.1 for more details about toxicity monitoring during the Phase I portion of the study

11.4 Phase II study: The primary goal of this portion of the study is to assess the 2-year PFS

rate in patients with newly diagnosed advanced stage diffuse large B-cell lymphoma. Secondary endpoints will include toxicity, overall survival, and response probability.

Sixty-five eligible patients accrued over 18 months with 24 months of additional follow-up

will be sufficient to estimate the 2-year PFS within this group to ± 0.13. Sehn et al., found 2-year PFS to be approximately 80% and 60% for patients with intermediate (1-2) and high (3-5) IPI scores, respectively. (21) Given these historical data and assuming that 50% of accrued patients will be in each IPI risk category, we expect 2-year PFS for R-CHOP to be 70%. Under these assumptions, an estimated 2-year PFS rate of 80% or greater for R-CHOP+vorinostat would be sufficient to warrant further investigation. The target value will be adjusted based on the observed frequency of prognostic groups. This design has a power of 0.90 and a significance level of 0.05. Assuming 65 eligible patients are accrued to the Phase II portion of this trial, we will be able to estimate the probability of any particular toxicity to within ± 0.13. Any adverse event occurring with at least a 5% probability is likely to be seen at least once (96% chance).

11.5 Correlative studies will explore relationship between baseline acetylation and T-cell

subsets and PFS, impact of vorinostat (SAHA)-R-CHOP on these characteristics, and correlation of histone acetylation status of tumor tissue and whole blood. The analyses will be exploratory in nature.

11.6 There is no formal data and safety monitoring committee for Phase II studies. Toxicity

and accrual monitoring are done routinely by the Study Coordinator, Study Statistician, and the Disease Committee Chair. Response monitoring is done by the Study Statistician and Study Coordinator. Accrual reports are generated weekly and formal toxicity reports are generated every 6 months. In addition, the Statistical Center, Adverse Event Coordinator at the Operations Office, and Executive Officer monitor toxicities on an ongoing basis.

12.0 DISCIPLINE REVIEW

12.1 Pathology Review

All patients registered to this study will undergo pathology review. The purpose of this review is to verify the histologic diagnosis of diffuse large B-cell lymphoma and to confirm CD20 expression for immunohistochemistry.


a. Pathology materials collection and submission instructions can be accessed on the SWOG Specimen Submission webpage (https://swog.org/Members/ClinicalTrials/Specimens/Lymphpath.asp).

b. Failure to submit a registered patient's pathology materials for pathology will

make the patient ineligible. c. If patient consents to future use of specimens, any remaining tissue will be

banked at the SWOG Specimen Repository – Solid Tissue, Myeloma and Lymphoma Division, Lab #201.

13.0 REGISTRATION GUIDELINES

13.1 Patients must be registered prior to initiation of treatment (no more than 3 working days prior to planned start of treatment).

13.2 The individual registering the patient must have completed the appropriate Southwest

Oncology Group Registration Worksheet. The completed form must be referred to during the registration but should not be submitted as part of the patient data. OPEN will also ask additional questions that are not present on the Southwest Oncology Group Registration Worksheet. The individual registering the patient must be prepared to provide answers to the following questions:

a. Institution CTEP ID

b. Protocol Number

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c. Registration Step d. Treating Investigator e. Credit Investigator f. Patient Initials g. Patient’s Date of Birth h. Patient SSN (SSN is desired, but optional. Do not enter invalid numbers.) i. Country of Residence j. ZIP Code k. Gender (select one):

• Female Gender • Male Gender

l. Ethnicity (select one): • Hispanic or Latino • Not Hispanic or Latino • Unknown

m. Method of Payment (select one): • Private Insurance • Medicare • Medicare and Private Insurance • Medicaid • Medicaid and Medicare • Military or Veterans Sponsored NOS • Military Sponsored (Including Champus & Tricare) • Veterans Sponsored • Self Pay (No Insurance) • No Means of Payment (No Insurance) • Other • Unknown

n. Race (select all that apply):

• American Indian or Alaska Native • Asian • Black or African American • Native Hawaiian or other Pacific Islander • White • Unknown

13.3 Registration procedures

a. All site staff will use OPEN to enroll patients to this study. OPEN is a web-based

application and can be accessed at https://open.ctsu.org, or from the OPEN tab on the CTSU members’ side of the website at https://www.ctsu.org, or from the OPEN Patient Registration link on the SWOG CRA Workbench.

b. Prior to accessing OPEN site staff should verify the following:

• All eligibility criteria have been met within the protocol stated

timeframes. Site staff should refer to Section 5.0 to verify eligibility.

• All patients have signed an appropriate consent form and HIPAA authorization form (if applicable).

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c. Access requirements for OPEN:

• Site staff will need to be registered with CTEP and have a valid and active CTEP-IAM account. This is the same account (user ID and password) used for the CTSU members' web site.

• To perform registrations on SWOG protocols you must have an

equivalent 'Registrar' role on the SWOG roster. Role assignments are handled through SWOG.

Note: The OPEN system will provide the site with a printable confirmation of registration and treatment information. Please print this confirmation for your records.

d. Further instructional information is provided on the OPEN tab on the CTSU members’ side of the website at https://www.ctsu.org or at https://open.ctsu.org. For any additional questions contact the CTSU Help Desk at 1-888-823-5923 or [email protected].

13.4 Exceptions to Southwest Oncology Group registration policies will not be permitted.

a. Patients must meet all eligibility requirements. b. Institutions must be identified as approved for registration. c. Registrations may not be cancelled. d. Late registrations (after initiation of treatment) will not be accepted.

14.0 DATA SUBMISSION SCHEDULE

14.1 Data must be submitted according to the protocol requirements for ALL patients registered, whether or not assigned treatment is administered, including patients deemed to be ineligible. Patients for whom documentation is inadequate to determine eligibility will generally be deemed ineligible.

14.2 Master forms are included in Section 18.0 and (with the exception of the sample consent

form and the Registration Worksheet) must be submitted to the Data Operations Center in Seattle. Data from approved SWOG institutions must be submitted on-line via the Web; see Section 14.3a for details. Exceptions to online data submission are patient-completed (e.g. Quality of Life) forms and source documents (e.g. pathology/operative/lab reports).

14.3 Data Submission Procedures.

a. Southwest Oncology Group institutions must submit data electronically via the

Web by using the SWOG CRA Workbench. To access the CRA Workbench, go to the SWOG Web site (http://swog.org) and logon to the Members Area. After you have logged on, click on the CRA Workbench link to access the home page for CRA Workbench website. Next, click on the Data Submission link and follow the instructions. For new users, the link to a "Starter Kit" of help files may be found by clicking on the Starter Kit link at the Members’ logon page.

To submit data via the web the following must be done (in order): 1. You are entered into the Southwest Oncology Group Roster and issued

a SWOG Roster ID Number,

Revised 12/23/10 S0806 Revised 3/23/11 Page 45 Revised 8/26/11 Revised 11/11/11

2. You are associated as an investigator or CRA/RN at the institution where the patient is being treated or followed, and

3. Your Web User Administrator has added you as a web user and has given you the appropriate system permissions to submit data for that institution.

For assistance with points 1 and 2 call the Operations Office at 210/614-8808. For point 3, contact your local Web User Administrator (refer to the "Who is my Web User Administrator?" function on the swog.org Members logon page). For other difficulties with the CRA Workbench, please email [email protected].

b. If you need to submit data that are not available for online data submission, the only alternative is via facsimile. Should the need for this occur, institutions may submit data via facsimile to 800/892-4007 or 206/342-1680 locally. Please do not use cover sheet for faxed data. Please make sure that each page of all faxed data include the SWOG patient number, study ID and patient initials.

14.4 WITHIN 7 DAYS AFTER REGISTRATION:

Submit a copy of the following:

a. S0806 Prestudy Form (Form #20649).

b. S0806 Baseline Abnormalities Form (Form #48989)

c. Lymphoma Baseline Tumor Assessment Form (Form #48031).

d. Pathology report confirming histology and phenotypes.

e. Baseline radiology report.

14.5 WITHIN 28 DAYS AFTER REGISTRATION (all Phase I and Phase II patients)

Submit histopathologic materials along with a copy of the pathology reports to the SWOG Specimen Repository – Solid Tissue, Myeloma and Lymphoma Division (see Section 12.0).

14.6 AT PRESTUDY AND DAY 9 OF CYCLE 1 (all Phase I and Phase II patients), if consent

is obtained:

• Submit tissue specimen at prestudy only (see Section 15.3a). • Submit whole blood specimens at prestudy and Day 9 of Cycle 1 (see Section 15.2). • (Optional) Submit core needle biopsies at Day 9 of Cycle 1 (see Section 15.3b).

14.7 AFTER EVERY WEEK ON PROTOCOL TREATMENT (PHASE I PORTION ONLY):

Submit the web-based S0806 Dose-Limiting Toxicity Rapid Reporting Form (Form #37980), which can be found on the CRA workbench (see Section 13.3). For further details regarding the rapid reporting system, see Section 15.1.

14.8 WITHIN 7 DAYS AFTER EACH CYCLE:

Submit a copy of the following:

a. S0806 Treatment Form (Form #8053)

b. S0806 Adverse Event Form (Form #12947), if patient is on the Phase II portion

14.9 WITHIN 14 DAYS OF DISCONTINUATION OF PROTOCOL TREATMENT:

Submit the Off Treatment Notice (Form #52393).


14.10 WITHIN 14 DAYS OF PROGRESSION OR RELAPSE:

Submit copies of the following:

a. Web-based S0806 Dose-Limiting Toxicity Rapid Reporting Form (Form #37980) (if patient is on the Phase I portion), which can be found on the CRA workbench (see Section 13.3);

or

S0806 Adverse Event Form (Form #12947) (if patient is on the Phase II portion)

b. S0806 Treatment Form (Form #8053), if the patient was still on protocol treatment

c. Lymphoma Follow-Up Tumor Assessment Form (Form #64395)

d. Follow-Up Form (Form #64587) 14.11 WITHIN 14 DAYS OF EACH DISEASE ASSESSMENT UNTIL PROGRESSION OR

RELAPSE: Submit the Lymphoma Follow-Up Tumor Assessment Form (Form #64395) and follow-up

radiology reports. 14.12 ONCE OFF PROTOCOL TREATMENT: EVERY SIX MONTHS FOR 2 YEARS, AND

ANNUALLY THEREAFTER UNTIL 5 YEARS AFTER REGISTRATION:

Submit the Follow-Up Form (Form #64587). 14.13 WITHIN 4 WEEKS OF KNOWLEDGE OF SUBSEQUENT MALIGNANCY:

Submit the Notice of Second Malignancy (Form #27456) documenting date, site, and method for determining malignancy.

14.14 WITHIN 4 WEEKS OF KNOWLEDGE OF DEATH:

Submit the Notice of Death (Form #49467) documenting death information. 15.0 SPECIAL INSTRUCTIONS

15.1 RAPID REPORTING OF VORINOSTAT-RELATED DOSE-LIMITING TOXICITIES FOR PHASE I PORTION OF TRIAL

Participation in the Phase I portion of the trial requires weekly reporting of dose-limiting toxicities on patients who have initiated vorinostat treatment. These toxicities must be reported using the web-based S0806 Dose-Limiting Toxicity Rapid Reporting Form (Form #37980), which can be found on the CRA workbench (see Section 13.3).

Institutional participation in the Phase I portion of the trial requires the identification of a contact CRA and back-up CRA. Prior to registration of the first patient, each participant must provide the contact and back-up CRA names, e-mail addresses, and phone numbers to the SWOG Data Operations Center. Participants will be responsible for keeping this information up-to-date and must notify the Lymphoma Data Coordinator (206/652-2267) of any changes.

The contact CRA and back-up CRA will receive weekly e-mails including a list of the dose-limiting toxicity forms that are overdue, currently due, or due in the next week. These e-mails will include a reply-to address and phone number to contact the Data Operations Center when questions arise. Upon activation of the Phase I portion of the


study, participating institutions will receive an e-mail with information on current dose level, as well as specifications for e-mail and conference call communication among investigators participating in the Phase I portion.

15.2 Directions for collecting and submitting whole blood and serum samples for correlative

studies

a. Institutions are required to offer patients the opportunity to consent to the submission of blood for translational medicine studies. If consent is granted, whole blood and serum must be submitted as described below.

b. Collection

Blood is to be collected at the following two time points: • After registration prior to beginning protocol treatment • Day 9 of Cycle 1 At each time point, collect the following: • Two 10 mL sodium heparin tubes (green-top tube, Vacutainer, no

anticoagulant)

On the same day as collected, ship as described in Section 15.2g. • At least 3 mL in gold-top tubes that are completely free of anti-coagulant

reagents. A list of recommended tubes manufactured by BD is provided below:

Cat# 367983 SST Tube with Silica Clot Activator, Polymer Gel, Silicone-Coated Interior 13 x 75 3.5mL Gold Top Cat# 367977 SST Tube with Silica Clot Activator, Polymer Gel, Silicone-Coated Interior 13 x 100 4.0mL Gold Top Cat# 367986 SST Tube with Silica Clot Activator, Polymer Gel, Silicone-Coated Interior 13 x 100 5.0mL Gold Top

Process serum as described in Section 15.2c, then ship as described in Section 15.2g.

c. Processing serum

The blood collected in the gold-top tube must be processed into serum as described below:

1. Gently invert 5 times to mix. 2. Allow whole blood samples to clot for 30 to 60 minutes at room

temperature. 3. The serum must be processed no later than 2 hours after collection

from the patient. 4. Centrifuge at 1100-1300 x g at 4°C for 10 minutes in a swing-bucket

rotor or 15 minutes in fixed-angle rotor, max brake, to separate the serum from the clotted blood.

5. Using a micropipettor, collect the serum without disturbing the gel barrier at the bottom of the tube and transfer serum in 50µL aliquots to a properly labeled 1.50mL flip-top microfuge tube. Be sure to aliquot all serum collected for each sample. If SST tubes are not being used, a gel barrier may not be present. If this is the case, do not disturb the red cell pellet when collecting the serum


6. Immediately freeze and store at -80oC in 50µL aliquots. The Day 1 and Day 9 serum may be batched and shipped together.

d. Specimen collection and submission instructions can be accessed on the SWOG

Specimen Submission webpage

(http://swog.org/Members/ClinicalTrials/Specimens/LymSpecimens.asp), or via the link on the S0806 protocol abstract page on the SWOG website (www.swog.org).

e. The Federal guidelines for shipment are as follows:

1. The specimen must be wrapped in an absorbable material.

2. The specimen must be placed in an AIRTIGHT container (like a

resealable bag).

3. Pack the resealable bag and specimen in a Styrofoam shipping container.

4. Pack the Styrofoam shipping container in a cardboard box.

5. The cardboard box must be marked as "BIOHAZARD".

f. All specimens for this study must be shipped by overnight express to the

following lab:

Lab #2: SWOG Lymphoma Repository – University of Arizona Arizona Health Science Center Department of Pathology, Room 5211 1501 N. Campbell Ave. Tucson, AZ 85724-5043 Contact: Yvette Frutiger / Lisa M. Rimsza, M.D. Phone: 520/626-7477 FAX: 520/626-6081 E-mail: [email protected]

NOTE: DO NOT SEND SPECIMENS ON FRIDAY. SEND MONDAY THROUGH THURSDAY ONLY!

g. Packaging and shipping

• Whole blood (two green-top tubes): Package according to the federal guidelines for shipment listed in Section 15.2e. Ship at ambient temperature on the same day as collected to the lab listed in Section 15.2f.

• Serum (frozen aliquots processed as described in Section 15.2c): Package

according to the federal guidelines for shipment listed in Section 15.2e. Ship on sufficient dry ice to maintain temperature. The Day 1 and Day 9 samples may be batched and shipped together. Ship to the lab listed in Section 15.2f.

h. Specimen collection kits are not being provided for this submission; sites will use

institutional supplies. i. If patient consents to future use of specimens, any remaining blood and serum

will be banked at the SWOG Specimen Repository – Solid Tissue, Myeloma and Lymphoma Division #201.


15.3 Directions for collecting and submitting tissue samples for correlative studies

a. Submission of tissue from prestudy biopsy

Institutions are required to offer patients the opportunity to consent to the submission of tissue from the prestudy biopsy for use in translational medicine studies. If consent is granted, submit tissue as described here. Paraffin samples will be collected at pre-treatment. If the paraffin block is sent for discipline review (see Section 12.0), no additional sample is required for the pretreatment sample. On the other hand, if cut slides are sent for discipline review, then 10 additional cut unstained slides are required.

b. Submission of tissue from day 9 biopsy Institutions are encouraged (but not required) to offer patients the opportunity to consent to the submission of tissue from an optional Day 9 biopsy for use in translational medicine studies. If consent is granted, submit tissue as described here. Day 9 Cycle 1 core needed biopsies are encouraged for collection. Core-needle biopsies (> 5 mm3, “pea size” to “almond size”) should be submitted in paraffin.

c. Package according to the federal guidelines for shipment listed in Section 15.2e and ship to the lab listed in Section 15.2f.

d. If patient consents to future use of specimens, any remaining tissue will be

banked at the SWOG Specimen Repository – Solid Tissue, Myeloma and Lymphoma Division, Lab #201.

16.0 ETHICAL AND REGULATORY CONSIDERATIONS

The following must be observed to comply with Food and Drug Administration regulations for the conduct and monitoring of clinical investigations; they also represent sound research practice: Informed Consent The principles of informed consent are described by Federal Regulatory Guidelines (Federal Register Vol. 46, No. 17, January 27, 1981, part 50) and the Office for Protection from Research Risks Reports: Protection of Human Subjects (Code of Federal Regulations 45 CFR 46). They must be followed to comply with FDA regulations for the conduct and monitoring of clinical investigations. Institutional Review This study must be approved by an appropriate institutional review committee as defined by Federal Regulatory Guidelines (Ref. Federal Register Vol. 46, No. 17, January 27, 1981, part 56) and the Office for Protection from Research Risks Reports: Protection of Human Subjects (Code of Federal Regulations 45 CFR 46).

S0806 Page 49a Revised TBD

Informed Consent The principles of informed consent are described by Federal Regulatory Guidelines (Federal Register Vol. 46, No. 17, January 27, 1981, part 50) and the Office for Protection from Research Risks Reports: Protection of Human Subjects (Code of Federal Regulations 45 CFR 46). They must be followed to comply with FDA regulations for the conduct and monitoring of clinical investigations. Institutional Review This study must be approved by an appropriate institutional review committee as defined by Federal Regulatory Guidelines (Ref. Federal Register Vol. 46, No. 17, January 27, 1981, part 56) and the Office for Protection from Research Risks Reports: Protection of Human Subjects (Code of Federal Regulations 45 CFR 46).


Drug Accountability An investigator is required to maintain adequate records of the disposition of investigational drugs according to procedures and requirements governing the use of investigational new drugs as described in the Code of Federal Regulations 21 CFR 312. Publication and Industry Contact The agent (hereinafter referred to as "Agent"), Vorinostat (SAHA), used in this protocol is provided to the NCI under a Clinical Trials Agreement (CTA) between Merck and Co., Inc. (hereinafter referred to as "Collaborator") and the NCI Division of Cancer Treatment and Diagnosis. Therefore, the following obligations/guidelines apply to the use of the Agent in this study: 1. Agent may not be used outside the scope of this protocol, nor can Agent be transferred

or licensed to any party not participating in the clinical study. Collaborator data for Agent are confidential and proprietary to the Collaborator and should be maintained as such by the investigators. The protocol documents for studies utilizing investigational Agents contain confidential information and should not be shared or distributed without the permission of the NCI. If a copy of this protocol is requested by a patient or patient’s family member participating on the study, the individual should sign a confidentiality agreement. A suitable model agreement can be downloaded from: http://ctep.cancer.gov.

2. For a clinical protocol where there is an investigational Agent used in combination with

another investigational Agent, each the subject of different CTAs or CRADAs, the access to and use of data by each Collaborator shall be as follows (data pertaining to such combination use shall hereinafter be referred to as "Multi-Party Data"):

a. NCI must provide all Collaborators with written notice regarding the existence

and nature of any agreements governing their collaboration with NIH, the design of the proposed combination protocol, and the existence of any obligations which would tend to restrict NCI's participation in the proposed combination protocol.

b. Each Collaborator shall agree to permit use of the Multi-Party Data from the

clinical trial by any other Collaborator to the extent necessary to allow said other Collaborator to develop, obtain regulatory approval or commercialize its own investigational Agent.

c. Any Collaborator having the right to use the Multi-Party Data from these trials

must agree in writing prior to the commencement of the trials that it will use the Multi-Party Data solely for development, regulatory approval, and commercialization of its own investigational Agent.

3. Clinical Trial Data and Results and Raw Data developed under a Collaborative

Agreement will be made available exclusively to Collaborator(s), the NCI, and the FDA, as appropriate and unless additional disclosure is required by law or court order. Additionally, all Clinical Data and Results and Raw Data will be collected, used and disclosed consistent with all applicable federal statutes and regulations for the protection of human subjects, including, if applicable, the Standards for Privacy of Individually Identifiable Health Information set forth in 45 C.F.R. Part 164.

4. When a Collaborator wishes to initiate a data request, the request should first be sent to

the NCI, who will then notify the appropriate investigators (Group Chair for cooperative group studies, or PI for other studies) of Collaborator's wish to contact them.


5. Any data provided to the Collaborator for Phase III studies must be in accordance with the guidelines and policies of the responsible Data Monitoring Committee (DMC), if there is a DMC for this clinical trial.

6. Any manuscripts reporting the results of this clinical trial must be provided to CTEP for immediate delivery to the Collaborator for advisory review and comment prior to submission for publication. Collaborator will have 30 days from the date of receipt for review. Collaborator shall have the right to request that publication be delayed for up to an additional 30 days in order to ensure that Collaborator's confidential and proprietary data, in addition to the Collaborator's intellectual property rights, are protected. Copies of abstracts must be provided to CTEP for forwarding to the Collaborator for courtesy review as soon as possible and preferably at least three (3) days prior to submission, but in any case, prior to presentation at the meeting or publication in the proceedings. Press releases and other media presentation must also be forwarded to CTEP prior to release. Copies of any manuscript, abstract and/or press release/media presentation should be sent to:

Regulatory Affairs Branch, CTEP, DCTD, NCI Executive Plaza North, Suite 7111 Bethesda, Maryland 20892 FAX: 301/402-1584 E-mail: [email protected]

The Regulatory Affairs Branch will then distribute them to the Collaborator. No publication, manuscript or other form of public disclosure shall contain any of the Collaborator's confidential/proprietary information.

Monitoring

This study will be monitored by the Clinical Data Update System (CDUS) Version 3.0. Cumulative CDUS data will be submitted quarterly to CTEP by electronic means. Reports are due January 31, April 30, July 31 and October 31.

16.1 Adverse Event Reporting Requirements

a. Purpose

Adverse event data collection and reporting, which are required as part of every clinical trial, are done to ensure the safety of patients enrolled in the studies as well as those who will enroll in future studies using similar agents. Adverse events are reported in a routine manner at scheduled times during a trial. (Directions for routine reporting are provided in Section 14.0.) Additionally, certain adverse events must be reported in an expedited manner to allow for timelier monitoring of patient safety and care. The following guidelines prescribe expedited adverse event reporting for this protocol. See also Appendix 19.1 for general and background information about expedited reporting.

b. Reporting methods

This study requires that expedited adverse event reporting use the NCI’s Adverse Event Expedited Reporting System (AdEERS). The NCI’s guidelines for AdEERS can be found at http://ctep.cancer.gov. An AdEERS report must be submitted to the Southwest Oncology Group Operations Office electronically via the AdEERS Web-based application located at http://ctep.cancer.gov.

A 24-hour notification is to be made to CTEP by telephone at 301/897-7497, only when internet connectivity is disrupted. Once internet connectivity is restored, an AE report submitted by phone must be entered electronically into AdEERS by the original submitter at the site.

S0806 Page 52

c. When to report an event in an expedited manner

Some adverse events require 24-hour notification (refer to Tables 16.1-16.2) via AdEERS. When the adverse event requires expedited reporting, submit the report within the number of calendar days of learning of the event specified in Table 16.1 or 16.2, as applicable.

d. Other recipients of adverse event reports

The Operations Office will forward reports and documentation to the appropriate regulatory agencies and drug companies as required. Adverse events determined to be reportable must also be reported according to local policy and procedures to the Institutional Review Board responsible for oversight of the patient.

e. Expedited reporting for investigational agents

Expedited reporting is required if the patient has received at least one dose of the investigational agent as part of the trial. Reporting requirements are provided in Tables 16.1 and 16.2. The investigational agent used in this study is vorinostat (SAHA). If there is any question about the reportability of an adverse event or if on-line AdEERS cannot be used, please telephone or email the SAE Specialist at the Operations Office, 210/614-8808 or [email protected], before preparing the report.

Table 16.1:

AdEERS Reporting Requirements for Adverse Events That Occur Within 30 Days1 of the Last Dose of the Investigational Agent on Phase I Trials

Phase 1 Trials

Grade 1

Grade 2

Grade 2

Grade 3

Grade 3 Grades 4 & 52

Unexpected Expected

Unexpected and

Expected

Unex-pected

Expected with Hospitali-

zation

without Hospitali-

zation

with Hospitali-

zation

without Hospitali-

zation

Unexpected and

Expected

Unrelated Unlikely

Not Required

Not Required

Not Required

10 Calendar

Days

Not Required

10 Calendar

Days

Not Required

24-Hour; 5 Calendar

Days Possible Probable Definite

Not Required

10 Calendar

Days

Not Required

24-Hour; 5 Calendar

Days

24-Hour; 5 Calendar

Days

10 Calendar

Days

Not Required

24-Hour; 5 Calendar

Days 1 Adverse events with attribution of possible, probable, or definite that occur greater than 30 days after

the last dose of treatment with an agent under a CTEP IND require reporting as follows: AdEERS 24-hour notification followed by complete report within 5 calendar days for:

• Grade 3 unexpected events with hospitalization or prolongation of hospitalization • Grade 4 unexpected events • Grade 5 expected events and unexpected events

2 Although an AdEERS 24-hour notification is not required for death clearly related to progressive disease, a full

report is required as outlined in the table. Please see exceptions below under section titled "Additional Instructions or Exceptions".

March 2005

S0806 Page 53

Note: All deaths on study require both routine and expedited reporting regardless of causality. Attribution to treatment or other cause must be provided.

• Expedited AE reporting timelines defined:

“24 hours; 5 calendar days” – The investigator must initially report the AE via AdEERS within 24 hours of learning of the event followed by a complete AdEERS report within 5 calendar days of the initial 24-hour report.

“10 calendar days” - A complete AdEERS report on the AE must be submitted within 10 calendar days of the investigator learning of the event.

• Any medical event equivalent to CTCAE Grade 3, 4, or 5 that precipitates

hospitalization (or prolongation of existing hospitalization) must be reported regardless of attribution and designation as expected or unexpected with the exception of any events identified as protocol-specific expedited adverse event reporting exclusions.

• Any event that results in persistent or significant disabilities/incapacities, congenital

anomalies, or birth defects must be reported via AdEERS if the event occurs following treatment with an agent under a CTEP IND.

• Use the NCI protocol number and the protocol-specific patient ID assigned during trial

registration on all reports. Table 16.2: Phase II and III Trials Utilizing an Agent under a CTEP IND: AdEERS Expedited Reporting Requirements for Adverse Events that Occur within 30 Days1 of the Last Dose of the Investigational Agent Vorinostat (SAHA) in this Study

Grade 1

Grade 2

Grade 2

Grade 3

Grade 3

Grades 4 & 52

Grades 4 & 52

Unexpected Expected

Unexpected and

Expected Unexpected Expected with

Hospitali-zation

without Hospitali-

zation

with Hospitali-

zation

without Hospitali-

zation

Unex-pected Expected

Unrelated Unlikely

Not Required

Not Required

Not Required

10 CalendarDays

Not Required

10 Calendar

Days

Not Required

10 Calendar

Days

10 Calendar

Days

Possible Probable Definite

Not Required

10 Calendar Days

Not Required

10 CalendarDays

10 Calendar

Days

10 Calendar

Days

Not Required

24-Hour; 5 Calendar

Days

10 Calendar

Days 1 Adverse events with attribution of possible, probable, or definite that occur greater than 30 days after the last dose of

treatment with an agent under a CTEP IND require reporting as follows: AdEERS 24-hour notification followed by complete report within 5 calendar days for:

• Grade 4 and Grade 5 unexpected events AdEERS 10 calendar day report:

• Grade 3 unexpected events with hospitalization or prolongation of hospitalization • Grade 5 expected events

2 Although an AdEERS 24-hour notification is not required for death clearly related to progressive disease, a full report is required as outlined in the table.

Please see exceptions in f. below, "Additional Instructions or Exceptions."

March 2005

S0806 Page 54

Note: All deaths on study require both routine and expedited reporting regardless of causality. Attribution to treatment or other cause must be provided.

• Expedited AE reporting timelines defined:

"24 hours; 5 calendar days" – The investigator must initially report the AE via AdEERS within 24 hours of learning of the event followed by a complete AdEERS report within 5 calendar days of the initial 24-hour report.

"10 calendar days" - A complete AdEERS report on the AE must be submitted within 10 calendar days of the investigator learning of the event.

• Any medical event equivalent to CTCAE Grade 3, 4, or 5 that

precipitates hospitalization (or prolongation of existing hospitalization) must be reported regardless of attribution and designation as expected or unexpected with the exception of any events identified as protocol-specific expedited adverse event reporting exclusions.

• Any event that results in persistent or significant disabilities/incapacities,

congenital anomalies, or birth defects must be reported via AdEERS if the event occurs following treatment with an agent under a CTEP IND.

• Use the NCI protocol number and the protocol-specific patient ID

assigned during trial registration on all reports. f. Additional Instructions or Exceptions to AdEERS Expedited Reporting

Requirements for Phase II and III Trials Utilizing an Agent under a CTEP-IND 1. Group-specific instructions

Submission of the on-line AdEERS report plus any necessary amendments generally completes the reporting requirements. You may, however, be asked to submit supporting clinical data to the Operations Office in order to complete the evaluation of the event. If requested, the specified data should be sent by fax to 210/614-0006. Note, however, that any documents checked in the Additional Information section of the AdEERS report must be submitted to CTEP per the instructions on that AdEERS web page.

2. For this study, the adverse events listed below also require expedited reporting via AdEERS: • Unintended Pregnancy (Grade 3) • Pregnancy, puerperium and perinatal conditions (Grade 1-5) In addition, copies of supporting documentation (including pregnancy confirmation) must be submitted to:

SWOG Operations Office ATTN: SAE Program 4201 Medical Drive, Suite 250 San Antonio, TX 78229

g. Reporting secondary AML/MDS/ALL

1. All cases of acute myeloid leukemia (AML), acute lymphocytic leukemia

(ALL), and myelodysplastic syndrome (MDS) that occur in patients on NCI-sponsored trials following chemotherapy for cancer must be reported in AdEERS.

S0806 Page 55

i. In protocols using CTCAE Version 4.0 for SAE reporting, three options are available to describe treatment-related events:

• Leukemia secondary to oncology chemotherapy • Myelodysplastic syndrome. NOTE: The only grading option

for "Myelodysplastic syndrome" is Grade 4, life-threatening. If reporting MDS that is other than Grade 4, use “Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other, (specify,__)” and insert MDS as the specify term.

• Treatment related secondary malignancy ii. In protocols using CTCAE Version 3.0 for SAE reporting, the

event(s) can be reported as “Secondary malignancy-Other (specify, ___)”. Report MDS as “Myelodysplasia,” in the BLOOD/BONE MARROW category.

iii. Secondary malignancies other than AML/ALL/MDS that are

related to protocol treatment must also be reported in AdEERS. iv. Non-treatment related cases of AML/ALL/MDS must be reported

as follows: In protocols using CTCAE Version 4.0 for SAE reporting, report as “Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other, specify” In protocols using CTCAE Version 3.0 for SAE reporting, report MDS as “Myelodysplasia” and Leukemias as “Blood/Bone Marrow - Other (Specify, __)”

For more information see: http://ctep.cancer.gov/protocolDevelopment/default.htm#adverse_events_adeers

2. The following supporting documentation must also be submitted within 30 days:

• a copy of the pathology report confirming the AML/ALL /MDS diagnosis

• (if available) a copy of the cytogenetics report Submit the Report and documentation to: Investigational Drug Branch and Southwest Oncology Group by fax at 301-230-0159 ATTN: SAE Program 4201 Medical Drive, Suite 250 San Antonio, Texas 78229 NOTE: If a patient has been enrolled in more than one NCI-sponsored study, the report must be submitted for the most recent trial.

S0806 Page 56

17.0 BIBLIOGRAPHY 1. Rimsza L, Roberts R, Miller T, et al. Loss of MHC class II gene and protein expression in diffuse

large B-cell lymphoma is related to decreased tumor immunosurveillance and poor patient survival regardless of other prognostic factors: a follow-up study from the Leukemia and Lymphoma Molecular Profiling Project. Blood 103:4251-8, 2004.

2. Rimsza L, Roberts R, Campo E, et al. Loss of major histocompatibility class II expression in non-

immune-privileged site diffuse large B-cell lymphoma is highly coordinated and not due to chromosomal deletions. Blood 107:1101-7, 2006.

3. Beresford G, Boss J. CIITA coordinates multiple histone acetylation modifications at the HLA-

DRA promoter. Nat ImmunoX 2:652-7, 2001. 4. Lee S, Bottaro A, Insel R. Activation of terminal B cell differentiation by inhibition of histone

deacetylation. Mol Immunol 39:923-32, 2003. 5. Richon V, Emiliani S, Verdin E, et al. A class of hybrid polar inducers of transformed cell

differentiation inhibits histone deacetylases. Proc Natl Acad Sci 95:3003-7, 1998. 6. Tao R, de Zoeten E, Ozkaynak E, et al. Deacetylase inhibition promotes the generation and

function of regulatory T cells. Nat Med 13:1299-307, 2007. 7. Johnson J, Pahuja A, Graham M, et al. Effects of histone deacetylase inhibitor SAHA on effector

and FOXP3+regulatory T cells in rhesus macaques. Transplant Proc 40:459-61, 2008. 8. Reddy P, Maeda Y, Hotary K, et al. Histone deacetylase inhibitor suberoylanilide hydroxamic acid

reduces acute graft-versus-host disease and preserves graft-versus-leukemia effect. Proc Natl Acad Sci 101:3921-6, 2004.

9. Li N, Zhao D, Kirschbaum M, et al. HDAC inhibitor reduces cytokine storm and facilitates

induction of chimerism that reverses lupus in anti-CD3 conditioning regimen. Proc Natl Acad Sci U S A 105:4796-801, 2008.

10. O'Connor O, Heaney M, Schwartz L, et al. Clinical experience with intravenous and oral

formulations of the novel histone deacetylase inhibitor suberoylanilide hydroxamic acid in patients with advanced hematologic malignancies. J Clin Oncol 24:166-173, 2006.

11. Duvic M, Talpur R, Ni X, et al. Phase 2 trial of oral vorinostat (suberoylanilide hydroxamic acid,

SAHA) for refractory cutaneous T-cell lymphoma (CTCL). Blood 109:31-39, 2007. 12. Crump M, Coiffier B, Jacobsen E, et al. Oral vorinostat (suberoylanilide hydroxamic acid, SAHA)

in relapsed diffuse large B-cell lymphoma (DLBCL): Final results of a phase II trial. Ann Oncol 19:964-8, 2008.

13. Kirschbaum M, Popplewell L, Nademanee A., et al. Phase 2 study of vorinostat (suberoylanilide

hydroxamic acid, SAHA) in relapsed or refractory indolent non-Hodgkin lymphoma. A California Cancer Consortium study. Blood 111:1564a, 2008.

14. Zhao W, Wang L, Liu Y, et al. Combined effects of histone deacetylase inhibitor and rituximab on

non-Hodgkin's B-lymphoma cells apoptosis. Exp Hematol 35:1801-11, 2007. 15. Georgakis G, Yazbeck V, Li Y, et al. The histone deacetylase inhibitor vorinostat (SAHA) induces

apoptosis and cell cycle arrest in Hodgkin lymphoma (HL) cell lines by altering several survival signaling pathways and synergizes with doxorubicin, gemcitabine and bortezomib. Blood (ASH Annual Meeting Abstracts) 108:2260, 2006.

16. Marchion D, Bicaku E, Daud A, et al. Sequence-specific potentiation of topoisomerase II

inhibitors by the histone deacetylase inhibitor suberoylanilide hydroxamic acid. J Cell Biochem 92:223-237, 2004.

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17. Munster PN, Marchion D, Thomas S, et al. Phase I trial of vorinostat and doxorubicin in solid tumours: histone deacetylase 2 expression as a predictive marker. Br J Cancer 101:1044-50, 2009.

18. Sanchez-Gonzalez B, Yang H, Bueso-Ramos C, et al. Antileukemia activity of the combination of

an anthracycline with a histone deacetylase inhibitor. Blood 108:1174-1182, 2006. 19. Kadia TM, Yang H, Ferrajoli A, et al. A phase I study of vorinostat in combination with idarubicin

in relapsed or refractory leukaemia. Br J Haematol 150(1):72-82, 2010. 20. Ramalingam S, Parise R, Ramananthan R, et al. Phase I and pharmacokinetic study of

vorinostat, a histone deacetylase inhibitor, in combination with carboplatin and paclitaxel for advanced solid malignancies. Clin Cancer Res 13:3605-3610, 2007.

21. Fakih MG, Pendyala L, Fetterly G, et al. A phase I, pharmacokinetic and pharmacodynamic study

on vorinostat in combination with 5-fluorouracil, leucovorin, and oxaliplatin in patients with refractory colorectal cancer. Clin Cancer Res 15:3189-95, 2009.

22. Sehn L, Berry B, Chhanabhai M, et al. The revised International Prognostic Index (R-IPI) is a

better predictor of outcome than the standard IPI for patients with diffuse large B-cell lymphoma treated with R-CHOP. Blood 109:1857-1861, 2007.

23. Coiffier B, Thieblemont C, Van Den Neste E, et al. Long-term outcome of patients in the LNH-

98.5 trial, the first randomized study comparing rituximab-CHOP to standard CHOP chemotherapy in DLBCL patients: a study by the Groupe d'Etudes des Lymphomes de l'Adulte. Blood 116(12):2040-5, 2010.

24. Morrison V, Weller E, Habermann T, et al. Maintenance rituximab (MR) compared to observation

(OBS) after R-CHOP or CHOP in older patients (pts) with diffuse large B-cell lymphoma (DLBCL): An Intergroup E4494/C9793 update. J Clin Oncol ASCO Annual Meeting Proceedings, 25(18S): 8011a, 2007.

25. Rimsza LM, Leblanc ML, Unger JM, et al. Gene expression predicts overall survival in paraffin-

embedded tissues of diffuse large B-cell lymphoma treated with R-CHOP. Blood 112:3425-33, 2008.

26. Cheson B, Pfistner B, Juweid M, et al. Revised response criteria for malignant lymphoma. J Clin

Oncol, 25:579-86, 2007.


18.0 MASTER FORMS SET

18.1 The Model Informed Consent Form is included in this section, preceded by "Notes for Local Institution Consent Form Authors" and "Notes for Local Investigators." The study - as well as the local consent form meeting the guidelines noted in these documents - must be reviewed and approved by the Institutional Review Board prior to registration and treatment of patients on this study.

18.2 This section includes copies of all data forms that must be completed for this study.

These include:

a. S0806 Registration Worksheet (Form #38032) b. S0806 Prestudy Form (Form #20649) c. S0806 Baseline Abnormalities Form (Form #48989) d. S0806 Treatment Form (Form #8053) e. S0806 Adverse Event Form (Form #12947) f. S0806 Dose-Limiting Toxicity Rapid Reporting Form (Form #37980) g. Lymphoma Baseline Tumor Assessment Form (Form #48031) h. Lymphoma Follow-Up Tumor Assessment Form (Form #64395) i. Follow-Up Form (Form #64587) j. Notice of Second Malignancy (Form #27456) k. Off Treatment Notice (Form #52393) l. Notice of Death (Form #49467)

S0806 Page 59

Informed Consent Model for S0806 *NOTES FOR LOCAL INSTITUTION INFORMED CONSENT AUTHORS: This model informed consent form has been reviewed by the DCT/NCI and is the official consent document for this study. Local IRB changes to this document are allowed. (Institutions should attempt to use sections of this document that are in bold type in their entirety.) Editorial changes to these sections may be made as long as they do not change information or intent. If the institutional IRB insists on making deletions or more substantive modifications to the risks or alternatives sections, they may be justified in writing by the investigator and approved by the IRB. Under these circumstances, the revised language, justification and a copy of the IRB minutes must be forwarded to the Southwest Oncology Group Operations Office for approval before a patient may be registered to this study. Please particularly note that the questions related to banking of specimens for future study are in bolded type and may not be changed in any way without prior approval from the Southwest Oncology Group Operations Office.

Readability Statistics: Flesch Reading Ease 52.2(targeted above 55) Flesch-Kincaid Grade Level 10.2(targeted below 8.5)

• Instructions and examples for informed consent authors are in [italics]. • A blank line, __________, indicates that the local investigator should provide the

appropriate information before the document is reviewed with the prospective research participant.

• The term "study doctor" has been used throughout the model because the local investigator for a cancer treatment trial is a physician. If this model is used for a trial in which the local investigator is not a physician, another appropriate term should be used instead of "study doctor".

• The dates of protocol updates in the header and in the text of the consent is for reference to this model only and should not be included in the informed consent form given to the prospective research participant.

• The local informed consent must state which parties may inspect the research records. This includes the NCI, the drug manufacturer for investigational studies, any companies or grantors that are providing study support (these will be listed in the protocol's model informed consent form) and the Southwest Oncology Group.

The "Southwest Oncology Group" must be listed as one of the parties that may inspect the research records in all protocol consent forms for which patient registration is being credited to the Southwest Oncology Group. This includes consent forms for studies where all patients are registered directly through the Southwest Oncology Group Data Operations Office, all intergroup studies for which the registration is being credited to the Southwest Oncology Group (whether the registration is through the SWOG Data Operations Office or directly through the other group), as well as consent forms for studies where patients are registered via CTSU and the registration is credited to the Southwest Oncology Group.

S0806 Page 60

• When changes to the protocol require revision of the informed consent document, the IRB should have a system that identifies the revised consent document, in order to preclude continued use of the older version and to identify file copies. An appropriate method to identify the current version of the consent is for the IRB to stamp the final copy of the consent document with the approval date. The stamped consent document is then photocopied for use. Other systems of identifying the current version of the consent such as adding a version or approval date are allowed as long as it is possible to determine during an audit that the patient signed the most current version of the consent form.

*NOTES FOR LOCAL INVESTIGATORS: • The goal of the informed consent process is to provide people with sufficient

information for making informed choices. The informed consent form provides a summary of the clinical study and the individual's rights as a research participant. It serves as a starting point for the necessary exchange of information between the investigator and potential research participant. This model for the informed consent form is only one part of the larger process of informed consent. For more information about informed consent, review the "Recommendations for the Development of Informed Consent Documents for Cancer Clinical Trials" prepared by the Comprehensive Working Group on Informed Consent in Cancer Clinical Trials for the National Cancer Institute. The Web site address for this document is http://cancer.gov/clinicaltrials/understanding/simplification-of-informed-consent-docs/

• A blank line, __________, indicates that the local investigator should provide the appropriate information before the document is reviewed with the prospective research participant.

• Suggestion for Local Investigators: An NCI pamphlet explaining clinical trials is available for your patients. The pamphlet is entitled: "If You Have Cancer…What You Should Know about Clinical Trials". This pamphlet may be ordered on the NCI Web site at http://cissecure.nci.nih.gov/ncipubs/details.asp?pid=1035 or call 1-800-4- CANCER (1-800-422-6237) to request a free copy.

• Optional feature for Local Investigators: Reference and attach drug sheets, pharmaceutical information for the public, or other material on risks. Check with your local IRB regarding review of additional materials.

*These notes for authors and investigators are instructional and should not be included in the informed consent form given to the prospective research participant.

S0806 Page 61

S0806, "A Phase I/II Trial of Vorinostat (SAHA) (NSC-701852) in Combination With Rituximab-CHOP in Patients With Newly Diagnosed Advanced Stage Diffuse Large B-Cell Lymphoma

(DLBCL)" This is a clinical trial, a type of research study. Your study doctor will explain the clinical trial to you. Clinical trials include only people who choose to take part. Please take your time to make your decision about taking part. You may discuss your decision with your friends and family. You can also discuss it with your health care team. If you have any questions, you can ask your study doctor for more explanation. You are being asked to take part in this study because you have cancer of the lymph nodes called diffuse large B-cell lymphoma.

Who is doing this study?

The Southwest Oncology Group (SWOG) is sponsoring this trial. SWOG is an adult cancer clinical trials organization. SWOG is funded through the National Cancer Institute, and its network consists of almost four thousand physicians at almost three hundred institutions throughout the United States. Your study doctor has met all requirements to be a member of SWOG and to perform National Cancer Institute-funded research through this Group.

Why is this study being done? The standard therapy of large cell lymphoma uses a combination of the drugs cyclophosphamide, doxorubicin, vincristine, and prednisone (called "CHOP") with the rituximab antibody. CHOP is a common chemotherapy for lymphoma. The rituximab antibody is a protein that targets specific cells that are related to your cancer. The combination of rituximab-CHOP chemotherapy has been used to treat patients with lymphoma and has been shown to be active against lymphoma. This experimental study is being done to test the best dose and safety for using vorinostat (SAHA) together with rituximab-CHOP. It is also being done to see if patients treated with the vorinostat-rituximab-CHOP chemotherapy will have longer lasting tumor shrinkage than patients treated with CHOP chemotherapy and rituximab alone. This study will be conducted in two parts. You will take part in either Part I or Part II, not both. In the first part of the study, patients will be treated with a specific dose of vorinostat along with the rituximab-CHOP chemotherapy. If this vorinostat dose causes bad side effects, it will be decreased as new patients take part in the study. Once the


maximum safe dose of vorinostat is decided, the first part of the study will end and the second part of the study will start. In the second part of the study, patients will be treated with the vorinostat dose (determined from Part I) and the CHOP-rituximab chemotherapy.

How many people will take part in the study? It is expected that about 10-30 patients will participate in the Phase I part of the study and about 65 patients will participate in the Phase II part of the study. Your study doctor will tell you whether you will take part in the first part of the study or the second part.

What will happen if I take part in this research study? Before you begin the study … You will need to have the following exams, tests or procedures to find out if you can be in the study. These exams, tests or procedures are part of regular cancer care and may be done even if you do not join the study. If you have had some of them recently, they may not need to be repeated. This will be up to your study doctor.

• Medical History and Physical Exam • Weight and Performance Status • Disease Assessment by CT scan and PET scan • ECHO/MUGA and EKG (scans to check heart function) • Routine laboratory blood tests (to measure your blood counts, blood clotting, electrolytes,

and liver and kidney function), including a Hepatitis B virus (HBV) screening (recommended for patients at high risk of infection)

• You will also have your bone marrow examined (called "bone marrow aspiration and biopsy") at the start of this study. Your skin over your hipbone will be numbed by a shot of local anesthetic (lidocaine) given just under your skin. A needle will be inserted through the numbed skin and into the hipbone. The bone marrow will be removed by using suction and a twisting motion of the needle. You may have minor discomfort, and minor infection is also possible. Sometimes allergic reactions to the anesthetic may occur. These are regular tests for many patients with lymphoma. The bone marrow will be looked at to find out if any lymphoma cells are present, and to determine the status of normal blood cells.

During the study … If the exams, tests and procedures show that you can be in the study, and you choose to take part, then you will need the following tests and procedures. They are part of regular cancer care.

• Your initial tumor biopsy sample will be sent to our pathology laboratory to confirm your diagnosis. Extra tests may be done on your tissue sample to classify your tumor type and to see if a certain protein (CD20) that is targeted with this therapy is present on your tumor cells.

• Routine laboratory blood tests: At Week 4, then every 3 weeks until you finish the study treatment

• Disease Assessment (by CT scan): Week 13, Week 26, and during follow-up. • EKG (to check heart function) at Weeks 4 and 16. (3/23/11)

S0806 Page 63

In the Phase I part of the study, the first 10 people to enter the study will be given a certain dose of vorinostat for Days 1-9. If more than 3 of these 10 people have serious side effects, then a lower dose of vorinostat will be used for the next 10 patients. If more than 3 of these next 10 people have serious side effects, then another 10 patients will be given the same dose of vorinostat but the duration of treatment will be reduced to Days 1-5. You should maintain adequate food and fluid intake while on this study. Your study doctor may encourage you to seek a nutritional consult. Vorinostat is a capsule that you will take by mouth. Your doctor will tell you how many capsules to take and when to take them. If possible, you should take vorinostat with food. You will receive a calendar to help you and your doctor keep track of the vorinostat capsules you take. It will be used to keep track of how much you take and any side effects you have. While on vorinostat treatment, you will receive the drugs cyclophosphamide, doxorubicin, vincristine, and rituximab through a needle in your vein on Day 3 of each treatment cycle. (A cycle in this study is 21 days long.) You will also receive medications before the rituximab to help control pain and prevent possible allergic reaction. Your doctor will decide what medications are needed for this. You will also take the drug prednisone by mouth (pills) on Days 3-7 of the cycle. This combination of drugs is known as CHOP-rituximab. It will take about 30-60 minutes to receive the cyclophosphamide, 5-20 minutes for the doxorubicin, and 5-15 minutes for the vincristine, and up to 6 hours to receive the rituximab. The vorinostat-rituximab-CHOP treatment will be repeated every 21 days for 8 cycles as long as your disease is not getting worse. In the Phase II part of the study, patients will be treated with vorinostat at the dose and duration considered to be safe (from the Phase I part of the study). If you participate in the Phase II part of the study, you will receive vorinostat-rituximab-CHOP combination therapy as outlined above. Standard medications will be used to help prevent side effects, such as nausea, fevers, and allergic reactions. Stool softeners will be given to prevent constipation. These medications do not require a prescription, and are commonly used during CHOP and rituximab therapy. In certain cases, your physician may recommend a medication to help prevent kidney problems from death of lymphoma cells ("tumor lysis"). Finally, in certain cases, your study doctor may suggest a medication to help your body produce red blood cells or white blood cells. In all cases, your physician will provide detailed instructions and information regarding these treatments.

How long will I be in the study? It will take you about 6 months to finish the vorinostat-rituximab-CHOP treatments. You will return to your around Week 26 for tests and scans. You will then return for a follow-up visit to your study doctor every 6 months for two years and then once a year after that for a maximum of 5 years (from the time you registered). Your study doctor may wish to see you more often. The follow-up evaluation tests that are standard of cancer care will include a medical history, physical examination, and scans to see whether your cancer has become worse.


Your study doctor may decide to take you off this study if your disease gets worse despite the treatment, the side effects of the treatment are too dangerous for you, new information about the treatment becomes available and this information suggests the treatment will be ineffective or unsafe for you. It is unlikely, but the study may be stopped early due to lack of funding.

Can I stop being in the study?

Yes. You can decide to stop at any time. Tell the study doctor if you are thinking about stopping or decide to stop. He or she will tell you how to stop safely. It is important to tell the study doctor if you are thinking about stopping so any risks from the treatment therapy can be evaluated by your doctor. Another reason to tell your doctor that you are thinking about stopping is to discuss what follow-up care and testing could be most helpful for you. The study doctor may stop you from taking part in this study at any time if he/she believes it is in your best interest, if you do not follow the study rules, or if the study is stopped.

What side effects or risks can I expect from being in the study? You may have side effects while on the study. Everyone taking part in the study will be watched carefully for any side effects. However, doctors don’t know all the side effects that may happen. Side effects may be mild or very serious. Your health care team may give you medicines to help lessen side effects. Many side effects go away soon after the completion of this experimental treatment study. In some cases, side effects can be serious, long lasting, or may never go away. You should talk to your study doctor about any side effects that you have while taking part in the study. Risks and side effects related to vorinostat include those that are: Likely (occurring in > 20% of patients)

• (moved to Less Likely 11/18/11) • Nausea or the urge to vomit • Vomiting • Diarrhea • Fatigue or tiredness • Lack of enough red blood cells (anemia) • Decreased number of a type of blood cell that helps to clot blood (platelet) • Loss of appetite

Less Likely (occurring in ≤ 20% of patients)

• Increased blood levels of creatinine (a substance normally eliminated by the kidneys into the urine)

• Increased blood sugar level • Belly pain • Weight loss (moved from Less Likely 11/18/11)


• Decrease in the total number of white blood cells (leukocytes) • Decreased number of a type of white blood cell (lymphocyte) • Decreased number of a type of white blood cell (neutrophil/granulocyte) • Decreased blood level of calcium • Decreased blood level of potassium • Dehydration (when your body does not have as much water and fluid as it should) • Fever • (deleted 11/18/11) • Hair loss • Constipation • Dry mouth • Taste changes • Decreased levels of a blood protein called albumin • Muscle weakness • Dizziness (or sensation of lightheadedness, unsteadiness, giddiness, spinning or

rocking) • Cough • Shortness of breath • (deleted 11/18/11) • Heartburn • (deleted 11/18/11) • Infection • Increased blood level of a liver enzyme (ALT/SGPT) • Increased blood level of a liver enzyme (AST/SGOT) • Increased blood level of a liver or bone enzyme (alkaline phosphatase) • Increased blood level of a liver pigment (bilirubin) often a sign of liver

problems • Decreased blood level of sodium • Decreased blood level of phosphate • Muscle spasms

Rare, but serious (occurring in < 3% of patients)

• Death of skin tissue Other considerations: Since vorinostat may cause loss of appetite and/or diarrhea leading to dehydration, you need to inform your study doctor immediately if you experience diarrhea or cannot eat or drink normally. If that happens, you may need intravenous fluids to treat dehydration. To prevent dehydration, patients should consume at least 2 liters of fluid orally, daily. If you are experiencing changed sense of taste, popsicles or Gatorade may be recommended. When applied to cells in plastic dishes, vorinostat caused damage to the cell’s genetic material (DNA). While the risks of this finding to you are unknown, some chemicals that cause similar effects in cells have been shown to cause new cancer when repeatedly administered to humans.

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Risks and side effects related to the antibody rituximab include the following: Likely:

• Chills • Fever • Reaction that can occur during or following infusion of the drug. The reaction may

include fever, chills, rash, low blood pressure, and difficulty breathing. • Decreased number of a type of white blood cell (lymphocyte)

Less Likely:

• Lack of enough red blood cells (anemia) • Thickening of blood/serum as found in Waldenstrom's macroglobulinemia (a cancer

of certain blood cells) • Fever associated with dangerously low levels of a type of white blood cell

(neutrophils) • Heart attack caused by a blockage of a blood vessel supplying part of the heart • Fast heartbeat; regular rhythm • Fast heartbeat usually originating in an area located above the ventricles • Belly pain • Diarrhea • Nausea or the urge to vomit • Vomiting • Swelling of the arms and/or legs • Fatigue or tiredness • Pain • Allergic reaction by your body to the drug product that can occur immediately or

may be delayed. The reaction may include hives, low blood pressure, wheezing, swelling of the throat, and difficulty breathing.

• Allergic reaction to certain medications, injected proteins, or antisera (blood product) used to treat certain medical conditions (such as an infectious or poisonous substance)

• Infection • Awakening of viruses which have been latent/dormant • Infection in HIV positive patients • Decreased number of a type of white blood cell (neutrophil/granulocyte) • Decreased number of a type of blood cell that help to clot blood (platelet) • Decrease in the total number of white blood cells (leukocytes) • Increased blood sugar level • Decreased blood level of calcium • Decreased blood level of potassium • Joint pain • Back pain • Muscle pain • Pain in the area of the tumor

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• Dizziness (or sensation of lightheadedness, unsteadiness, or giddiness) • Headache or head pain • Abnormal drowsiness or sluggishness, an unusual lack of energy • Convulsion or seizure • Sudden or traumatic injury to the kidney • Stuffy or runny nose, sneezing • Sudden constriction of the small airways of the lung that can cause wheezing and

shortness of breath • Cough • Shortness of breath • Decrease in the oxygen supply to a tissue • Inflammation of the lungs that may cause difficulty breathing and can be life-

threatening • Sore throat • Excess sweating • Itching • Skin rash with the presence of macules (flat discolored area) and papules (raised

bump) • Swelling of body tissue underneath the skin • Hives • Sudden reddening of the face and/or neck • High blood pressure • Low blood pressure

Rare but Serious:

• Serious, life-threatening allergic reaction requiring immediate medical treatment by your doctor. The reaction may include extremely low blood pressure, swelling of the throat, difficulty breathing, and loss of consciousness.

• Group of signs and symptoms due to rapid breakdown of tumor that can occur after treatment of cancer has started that causes increased levels of blood potassium, uric acid, and phosphate, decreased levels of blood calcium, and kidney failure

• Disease affecting brain tissue, caused by JC virus • Severe potentially life-threatening damage to the lungs which can lead to fluid in the

lungs • Severe reaction of the skin and gut lining that may include rash and shedding or

death of tissue • Potentially life-threatening condition affecting less than 10% of the skin in which

cell death causes the epidermis (outer layer) to separate from the dermis (middle layer)

• Life-threatening condition affecting greater than 30% of the skin in which cell death causes the epidermis (outer layer) to separate from the dermis (middle layer)

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Risks and side effects related to the CHOP chemotherapy treatment (cyclophosphamide, doxorubicin, vincristine, prednisone) include the following: Likely (occurring in > 20% of patients)

• Nausea/vomiting • Hair loss • Less appetite • Blood cell counts go down • Swelling/puffy appearance (face/stomach area)

Less Likely (occurring in ≤ 20% of patients)

• Allergic reaction (like rash, itching, swelling, cough, lowered blood pressure) • Inflammation of the blood vessels in the skin where the drugs are given • Sores in the mouth • Skin and nails change color • Fingernails and toenails become loose • Flushing • Itching of skin • Headache • Stomach pain • Jaw pain • Weak bones • Diarrhea/constipation • Fever • Infection • Chills • Tiredness • Lower or higher blood pressure • Muscle weakness • Tingling in the arms and legs • Itchy, swollen eyes • Watery eyes • Changes in eyesight • Changes in tests that measure heart function • Bladder irritation (avoided by drinking 8-10 glasses of water a day) • Change in color of urine • Dizziness • Mood swings/depression • Changes in personality • Menstrual changes

Rare, but serious (occurring in < 3% of patients) • Scarring of lungs/shortness of breath • Shaking • Heart failure

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• Chance of blood cancer • Dehydration requiring intravenous fluids • Pneumonia which may require antibiotics • Condition in which the lens of the eye becomes cloudy (cataracts) • High pressure within the eyeball (glaucoma) • Injection site reaction • Your white blood cell counts may become very low from the treatment. You may be

given a shot of white blood cell growth factor to help prevent this risk. If you get fever during the time your blood counts are low, you may require antibiotic therapy, or admission to the hospital. Severe, life-threatening infections may occur under these circumstances. Your physician will provide detailed instructions on what to do if you get fever.

Reproductive risks: You should not become pregnant or father a baby while on this study because the drugs in this study can affect an unborn baby. Women should not breastfeed a baby while on this study. It is important you understand that you need to use birth control while on this study. Check with your study doctor about what kind of birth control methods to use and how long to use them. Some methods might not be approved for use in this study. For more information about risks and side effects, ask your study doctor.

Are there benefits to taking part in the study? Taking part in this study may or may not make your health better. While doctors hope the study treatment will be more useful against this type of cancer compared to the usual treatment, there is no proof of this yet. We do know that the information from this study will help doctors learn more about this therapy as a treatment for cancer. This information could help future cancer patients.

What other choices do I have if I do not take part in this study? Your other choices may include:

• Getting treatment or care for your cancer without being in a study • Taking part in another study • Getting no treatment

Talk to your doctor about your choices before you decide if you will take part in this study.

Will my medical information be kept private? We will do our best to make sure that the personal information in your medical record will be kept private. However, we cannot guarantee total privacy. Your personal information may be given out if required by law. If information from this study is published or presented at scientific meetings, your name and other personal information will not be used.

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Organizations that may look at and/or copy your medical records for research, quality assurance, and data analysis include:

• Your local Institutional Review Board (IRB) • The National Cancer Institute (NCI) • The Food and Drug Administration (FDA), involved in keeping research safe for people • The Southwest Oncology Group • Qualified representatives of Merck Inc., the manufacturer of vorinostat (SAHA)

[Note to Local Investigators: The NCI has recommended that HIPAA regulations be addressed by the local institution. The regulations may or may not be included in the informed consent form depending on local institutional policy.]

What are the costs of taking part in this study? You and/or your health plan/ insurance company will need to pay for some or all of the costs of treating your cancer in this study. Some health plans will not pay these costs for people taking part in studies. Check with your health plan or insurance company to find out what they will pay for. Taking part in this study may or may not cost your insurance company more than the cost of getting regular cancer treatment. Administration of the drug will be (provided free of charge/charged in the usual way). The parts of the research consisting of keeping research records will be paid by those organizing and conducting the research. The research requires that you receive certain standard medical tests and examinations. These standard tests and examinations will be charged in the usual way/provided at a reduced rate (local institutions must choose the option that best fits the hospital's situation). The Division of Cancer Treatment and Diagnosis, National Cancer Institute will provide you with the investigational agent vorinostat at no cost to you while you are participating in this study. However, if you should need to take the study agent much longer than is usual, it is possible that the free supply of study agent given to the NCI could run out. If this happens, your study doctor will discuss with you how to obtain additional drug from the manufacturer and you may be asked to pay for it. The cyclophosphamide, doxorubicin, vincristine, prednisone and rituximab are commercially available and will need to be paid for by you or your insurance. You will not be paid for taking part in this study. For more information on clinical trials and insurance coverage, you can visit the National Cancer Institute’s Web site at http://cancer.gov/clinicaltrials/understanding/insurance-coverage . You can print a copy of the "Clinical Trials and Insurance Coverage" information from this Web site. Another way to get the information is to call 1-800-4-CANCER (1-800-422-6237) and ask them to send you a free copy.

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What happens if I am injured because I took part in this study? It is important that you tell your study doctor, __________________ [investigator’s name(s)], if you feel that you have been injured because of taking part in this study. You can tell the doctor in person or call him/her at __________________ [telephone number]. You will get medical treatment if you are injured as a result of taking part in this study. You and/or your health plan will be charged for this treatment. The study will not pay for medical treatment.

What are my rights if I take part in this study? Taking part in this study is your choice. You may choose either to take part or not to take part in the study. If you decide to take part in this study, you may leave the study at any time. No matter what decision you make, there will be no penalty to you and you will not lose any of your regular benefits. Leaving the study will not affect your medical care. You can still get your medical care from our institution. We will tell you about new information or changes in the study that may affect your health or your willingness to continue in the study. In the case of injury resulting from this study, you do not lose any of your legal rights to seek payment by signing this form.

Who can answer my questions about the study? You can talk to your study doctor about any questions or concerns you have about this study. Contact your study doctor __________________ [name(s)] at __________________ [telephone number]. For questions about your rights while taking part in this study, call the ________________________ [name of center] Institutional Review Board (a group of people who review the research to protect your rights) at __________________ (telephone number). [Note to Local Investigator: Contact information for patient representatives or other individuals in a local institution who are not on the IRB or research team but take calls regarding clinical trial questions can be listed here.] Please note: This section of the informed consent form is about additional research studies that are being done with people who are taking part in the main study. You may take part in these additional studies if you want to. You can still be a part of the main study even if you say 'no' to taking part in any of these additional studies.


You can say "yes" or "no" to each of the following studies. Please mark your choice for each study. 1. Future Contact

Occasionally, researchers working with the Southwest Oncology Group (SWOG) may have another research idea that relates to people who were on a SWOG study. In some cases, to carry out the new research, we would need to contact participants in a particular study. You can agree or not agree to future contact. I agree to allow my study doctor, or someone approved by my study doctor, to contact me regarding future research involving my participation in this study. Yes No

2. Submission of blood for evaluation of immune system proteins and cells

Note to sites: This section refers to the blood and serum submission described in Section 15.2 of the protocol. Sites are required to offer patients the opportunity to consent to this. If you agree below, you will have additional blood drawn (about 5 teaspoons) at two time points: before you begin the study treatment and on Day 9. This blood will be sent to an outside lab to study MHC Class II proteins and CD8+ tumor infiltrating lymphocytes (TIL). The research that will be done with your blood is not designed to help you specifically. It might help people who have cancer and other diseases in the future. Reports about research done with your blood will not be given to you or your doctor. These reports will not be put in your health record. The research will not have an effect on your care. Neither you nor your insurance will be charged for this research. I agree to have my blood submitted for the evaluation of immune system proteins and cells. Yes No

3. Submission of original tumor biopsy for evaluation of immune system proteins and cells

Note to sites: This section refers to the tissue submission described in Section 15.3a of the protocol. (11/11/11) Sites are required to offer patients the opportunity to consent to this. If you agree below, part of your original tumor biopsy will be sent to an outside lab to study MHC Class II proteins and CD8+ tumor infiltrating lymphocytes (TIL). You will not need to have another biopsy for this. The research that will be done with your tissue is not designed to help you specifically. It might help people who have cancer and other diseases in the future. Reports about research done with your tissue will not be given to you or your doctor. These reports will not be put in your health record. The research will not have an effect on your care. Neither you nor your insurance will be charged for this research.


I agree to have part of my original tumor biopsy submitted for the evaluation of immune system proteins and cells. Yes No

4. Submission of on-study tumor biopsy for evaluation of immune system proteins and cells

Note to sites: This additional submission is requested only from patients who have a matched prestudy specimen available (i.e., those who responded “yes” to question #3 above). This section refers to the tissue submission described in Section 15.3b of the protocol. (11/11/11) Sites are encouraged, but not required, to offer patients the opportunity to consent to this. If you agree below, you will have a biopsy on Day 9 of the study. The cost of the Day 9 biopsy procedure will be covered up to a defined amount. (12/22/10) Tissue from this biopsy will be sent to an outside lab to study MHC Class II proteins and CD8+ tumor infiltrating lymphocytes (TIL). You will not need to have another biopsy for this. The research that will be done with your tissue is not designed to help you specifically. It might help people who have cancer and other diseases in the future. Reports about research done with your tissue will not be given to you or your doctor. These reports will not be put in your health record. The research will not have an effect on your care. Neither you nor your insurance will be charged for this research. I agree to have tissue from an on-study biopsy submitted for the evaluation of immune system proteins and cells. Yes No

5. Banking of specimens for use in future, unspecified research

Note to sites: This section applies to patients who responded “yes” to any of the specimen submission questions above. As described above, some of your tumor tissue and/or a blood sample will be sent to a lab to study the biology of your cancer. We would like to keep some of the specimens that are left over for future research. If you agree, these specimens will be kept and may be used in research to learn more about cancer and other diseases. Please read the information sheet called "How are Specimens Used for Research" to learn more about specimen research. (Section deleted 11/11/11)

S0806 Page 74

The research that may be done with your specimens are not designed specifically to help you. It might help people who have cancer and other diseases in the future.

Reports about research done with your specimens will not be given to you or your doctor. These reports will not be put in your health record. The research will not have an effect on your care.

Things to Think About

The choice to let us keep the left over specimens for future research is up to you. No matter what you decide to do, it will not affect your care.

If you decide now that your specimens can be kept for research, you can change your mind at any time. Just contact us and let us know that you do not want us to use your tissue. Then any specimens that remain will no longer be used for research.

In the future, people who do research may need to know more about your health. While the Southwest Oncology Group may give them reports about your health, it will not give them your name, address, phone number, or any other information that will let the researchers know who you are.

Sometimes specimens are used for genetic research (about diseases that are passed on in families). Even if your specimens is used for this kind of research, the results will not be put in your health records.

Your specimens will be used only for research and will not be sold. The research done with your specimens may help to develop new products in the future.

Benefits

The benefits of research using tissue include learning more about what causes cancer and other diseases, how to prevent them, and how to treat them.

Risks

The greatest risk to you is the release of information from your health records. We will do our best to make sure that your personal information will be kept private. The chance that this information will be given to someone else is very small. Making Your Choice

Please read each sentence below and think about your choice. After reading each sentence, circle "Yes" or "No." If you have any questions, please talk to your doctor or nurse, or call the research review board at IRB's phone number.

No matter what you decide to do, it will not affect your care.

a. My specimens may be kept for use in research to learn about, prevent, treat or cure cancer.

Yes No

b. My specimens may be kept for use in research about other health problems (for example: diabetes, Alzheimer's disease, or heart disease).

Yes No

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c. Someone may contact me in the future to ask me to allow other uses of my specimens.

Yes No

If you decide to withdraw your specimens from a Southwest Oncology Group Specimen Repository in the future, a written withdrawal of consent should be submitted through your study doctor to the Southwest Oncology Group Operations Office. Please designate in the written withdrawal whether you would prefer to have the specimens destroyed or returned to the study doctor.

Where can I get more information? You may call the National Cancer Institute's Cancer Information Service at:

1-800-4-CANCER (1-800-422-6237) or TTY: 1-800-332-8615

You may also visit the NCI Web site at http://cancer.gov/

• For NCI’s clinical trials information, go to: http://cancer.gov/clinicaltrials/ • For NCI’s general information about cancer, go to http://cancer.gov/cancerinfo/

You will get a copy of this form. If you want more information about this study, ask your study doctor.

Signature I have been given a copy of all _____ [insert total of number of pages] pages of this form. I have read it or it has been read to me. I understand the information and have had my questions answered. I agree to take part in this study.

Participant ________________________________

Date _____________________________________

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Specimen Consent Supplemental Sheets How are Specimens Used for Research? Where do specimens come from? A specimen may be from a blood sample or from bone marrow, skin, toenails or other body materials. People who are trained to handle specimens and protect donors' rights make sure that the highest standards of quality control are followed by the Southwest Oncology Group. Your doctor does not work for the Southwest Oncology Group, but has agreed to help collect specimens from many patients. Many doctors across the country are helping in the same way. Why do people do research with specimens? Research with specimens can help to find out more about what causes cancer, how to prevent it, how to treat it, and how to cure it. Research using specimens can also answer other health questions. Some of these include finding the causes of diabetes and heart disease, or finding genetic links to Alzheimer's. What type of research will be done with my specimen? Many different kinds of studies use specimens. Some researchers may develop new tests to find diseases. Others may develop new ways to treat or even cure diseases. In the future, some of the research may help to develop new products, such as tests and drugs. Some research looks at diseases that are passed on in families (called genetic research). Research done with your specimen may look for genetic causes and signs of disease. How do researchers get the specimen? Researchers from universities, hospitals, and other health organizations conduct research using specimens. They contact the Southwest Oncology Group and request samples for their studies. The Southwest Oncology Group reviews the way that these studies will be done, and decides if any of the samples can be used. The Southwest Oncology Group gets the specimen and information about you from your hospital, and sends the specimen samples and some information about you to the researcher. The Southwest Oncology Group will not send your name, address, phone number, social security number or any other identifying information to the researcher. Will I find out the results of the research using my specimen? You will not receive the results of research done with your specimen. This is because research can take a long time and must use specimen samples from many people before results are known. Results from research using your specimen may not be ready for many years and will not affect your care right now, but they may be helpful to people like you in the future. Why do you need information from my health records? In order to do research with your specimen, researchers may need to know some things about you. (For example: Are you male or female? What is your race or ethnic group? How old are you? Have you ever smoked?) This helps researchers answer questions about diseases. The information that will be given to the researcher may include your age, sex, race, diagnosis, treatments and family history. This information is collected by your hospital from your health record and sent to the Southwest Oncology Group. If more information is needed, the Southwest Oncology Group will send it to the researcher. Will my name be attached to the records that are given to the researcher? No. Your name, address, phone number and anything else that could identify you will be removed before they go the researcher. The researcher will not know who you are.

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How could the records be used in ways that might be harmful to me? Sometimes, health records have been used against patients and their families. For example, insurance companies may deny a patient insurance or employers may not hire someone with a certain illness (such as AIDS or cancer). The results of genetic research may not apply only to you, but to your family members too. For disease caused by gene changes, the information in one person's health record could be used against family members. How am I protected? The Southwest Oncology Group is in charge of making sure that information about you is kept private. The Southwest Oncology Group will take careful steps to prevent misuse of records. Your name, address, phone number and any other identifying information will be taken off anything associated with your specimen before it is given to the researcher. This would make it very difficult for any research results to be linked to you or your family. Also, people outside the research process will not have access to results about any one person which will help to protect your privacy. What if I have more questions? If you have any questions, please talk to your doctor or nurse, or call our research review board at (Insert IRB's Phone Number).

11/15/2010

Page 1 of 1SOUTHWEST ONCOLOGY GROUP

S0806 REGISTRATION WORKSHEET

Activation Date: November 15, 2010

Registration Step 1

Last Amended Date:

INSTRUCTIONS: All of the information on this Registration Worksheet and the Protocol Eligibility Section must be answered appropriately for a

patient to be considered eligible for registration. This Registration Worksheet must be entirely filled out and referred to during the registration. Do

NOT submit this worksheet as part of the patient data.

SWOG Patient ID Status: New Patient Previous Patient: SWOG Patient ID:

If the patient has a SWOG Patient ID assigned by a prior registration or Specimen Tracking, choose "Previous Patient" and use that number.

SWOG PATIENT ID

DEMOGRAPHY

Full names preferred, initials OK

Patient Last Name:

Patient Middle Name:

Patient First Name:

FOR SWOG INSTITUTIONS

Registrar's SWOG Roster ID Number:

SWOG Investigator Number:

SWOG Treating Institution Number:

A PHASE I/II TRIAL OF SUBEROYLANILIDE HYDROXAMIC ACID (SAHA)(NSC-701852) IN COMBINATION WITH RITUXIMAB-CHOP IN PATIENTSWITH NEWLY DIAGNOSED ADVANCED STAGE DIFFUSE LARGEB-CELL LYMPHOMA (DLBCL)

Indicate how the patient answered the following questions on the consent form

My specimens may be kept for use in research to learn about, prevent, treat, or cure cancer.

My specimens may be kept for use in research about other health problems (for example:diabetes, Alzheimer's disease, or heart disease).

Someone may contact me in the future to ask me to allow other uses of my specimens.

I agree to allow my study doctor, or someone approved by my study doctor, to contact me

regarding future research involving my participation in this study.

I agree to have my blood submitted for the evaluation of immune system proteins and cells.

Yes No

Yes No

Yes No

Yes No

Yes No

PATIENT INFORMATION

Date Informed Consent Signed: / /

Date HIPAA Authorization signed: / /

Projected Start Date of Treatment: / /

(Not required if Country of Residence is not USA)

I agree to have part of my original tumor biopsy submitted for the evaluation of immune system

proteins and cells.Yes No

I agree to have tissue from an on-study biopsy submitted for the evaluation of immune system

proteins and cells.Yes No

Patient Eligibility

Has the Southwest Oncology Group Registration Worksheet been completed entirely and is the

patient eligible according to the current version of protocol section 5.0?Yes No

38032

SOUTHWEST ONCOLOGY GROUPS0806 PRESTUDY FORM

Page 1 of 2

Patient Initials (L, F M)

4/1/2011

continued on next page

Does the patient have bulky disease (any mass 10 cm in diameter or a mediastinal mass > 1/3 chest diameter)?


Page 1 of 2

PhysicianInstitution / Affiliate


SWOG Patient ID

Instructions: Submit this form within 14 days of registration. All dates are MONTH, DAY, YEAR. Explain any blank fields or blank

dates in the Comments section. Place an X in appropriate boxes. Circle AMENDED items in red and write AMENDED across topof form.

4/1/2011

(PS0806)

SWOG Study No. S 0 8 0 6 Registration Step 1

ELIGIBILITY VERIFICATION:Each of the fields below corresponds to a criterion in Section 5 and must be completed for patient to be eligible.

PATIENT AND DISEASE DESCRIPTION

Performance status:

Symptoms: A (No Symptoms) B (Fever, Weight Loss, and/or Night Sweats)

Stage of disease at diagnosis: II III IV

Date of unilateral or bilateral bone marrow biopsy and aspirate: / /

No Yes

Result: Positive Negative

Hematologic:

ANC

Platelets

If ANC 1000/mcL and/or platelets 100,000/mcL, is this due tobone marrow infiltration by lymphoma?

If Yes, bone marrow involvement must be documented onLymphoma Baseline Tumor Assessment Form

WBC

Lymphocytopenia (% of total WBC)

Hemoglobin

Collection date:

LABORATORY VALUES Document values in units listed

Date of first pathologic diagnosis: / /

/ /

≥≥≥≥

Were any laboratory or radiographic tests performed to assess CNS involvement? No Yes

Result: Positive Negative

Date of tests to assess CNS involvement: / /

/ mcL,

/ mcL,

x 10 / mcL. ³

/ /

/ /

/ /

g/dL. / /

Yes No

≤≤≤≤≤≤≤≤

Height: cm

SWOG Patient ID

20649


Page 2 of 2


4/1/2011

LDH:

Cardiac:

Ejection fraction (select one)

LABORATORY VALUES, continued Collection date:


U/L ULN U/L / /

MUGA ECHO

% / /

Collection date:

ADDITIONAL PRESTUDY DATA:

If Yes, select all that apply:

Is there current extranodal involvement? No Yes

CURRENT EXTRANODAL INVOLVEMENT

Bone Marrow

GI Tract

Lung

Other:

Liver CNS/Brain

Comments:

SWOG Patient ID

20649

Comments:

SOUTHWEST ONCOLOGY GROUPS0806 BASELINE ABNORMALITIES FORM Page 1 of 1

Instructions: Using CTCAE 4.0 Grade definitions, please grade any abnormalities or conditions present PRIOR toprotocol treatment. Circle AMENDED items in red and write AMENDED across top of form.

11/15/2010(BASEAB)

SWOG Patient ID SWOG Study No. S 0 8 0 6 Registration Step 1


Institution/Affiliate Physician

Intracranial hemorrhage

Peripheral motor neuropathy

Peripheral sensory neuropathy

Insomnia

Acute kidney injury

Urinary frequency

Genital edema

Cough

Dyspnea

Hypoxia

Alopecia

Hyperhidrosis

Rash maculo-papular

Hypertension

Hypotension

Thromboembolic event

Creatinine increased




Weight loss


Anorexia

Dehydration

Hyperglycemia

Hypoglycemia

Hyponatremia

Hypophosphatemia

Tumor lysis syndrome

Arthralgia

Bone pain

Fibrosis deep connective tissue

Generalized muscle weakness

Myalgia

Dizziness

Dysgeusia

Headache

CTC Adverse Event

Term (Pre-treatment)

CTC Adverse Event

Term (Pre-treatment)CTC Adverse Event

Term (Pre-treatment)

CTCAE (4.0)

Grade(1 - 4)

CTCAE (4.0)

Grade(1 - 4)

CTCAE (4.0)

Grade(1 - 4)

CTC Adverse Event Term, Other (pre-treatment)

(specify using CTCAE 4.0 terminology):

Anemia

Febrile neutropenia

Left ventricular systolic dysfunction

Constipation

Diarrhea

Dry mouth

Nausea

Vomiting

Chills

Edema face

Edema limbs

Edema trunk

Fatigue

Fever

Localized edema

Allergic reaction

Lung infection

Activated partial thromboplastintime prolongedAlanine aminotransferaseincreasedAspartate aminotransferaseincreasedBlood bilirubin increased

48989

SOUTHWEST ONCOLOGY GROUPS0806 TREATMENT FORM

11/15/2010

Page 1 of 2

Instructions: Please complete this form after every cycle (1 cycle = 21 days of treatment). If an agent listed is not to beadministered for a specific cycle or assigned treatment arm, then leave the entire row blank for that agent. If any assigned agentwas not administered during this reporting period then the entire line should be completed, using "0" where necessary. All dates are

MONTH, DAY, YEAR. Explain any blank dates or fields in a Comments section. Place an X in appropriate boxes. Circle AMENDEDitems in red and write AMENDED across the top of the form.


SWOG Patient ID

11/15/2010


(L, F M)Patient Initials

Page 1 of 2

(TX0806)

Cycle Number:


TREATMENT FOR THIS CYCLE


No

Yes, planned (per protocol guidelines), complete the modification fields below

Yes, unplanned (not per protocol guidelines), complete the modification fields below

Were there any dose modifications or additions/omissions to protocol treatment?

BSA (first day this cycle): . 2m Weight: . kg

Date of last treatment: / /Treatment start date: / /

Reporting period end date: / /

Reporting period start date: / /

(submit Follow Up Form and Off Treatment Notice)

Has the patient progressed per the definition in Section 10.0 of the protocol?

No Yes

(submit Notice of Death)

Vital Status: Alive Dead Date of Last Contact or Death: / /STATUS

Rituximab

SAHA (Vorinostat)

Cyclophosphamide

Doxorubicin

Vincristine

Prednisone

mg

mgmg/m2

Agent Name

Dose Plannedat Cycle Start

Dose Delivered at Cycle End Total Dose Given Modifications

@

@ Agent Dose Modification Codes1 = No dose modification2 = Dose held3 = Dose delayed

4 = Dose reduced5 = Dose delayed and reduced6 = Drug discontinued

7 = Drug increased (error)8 = Drug given too early9 = Drug re-escalation

(Day 1 of next cycle. If final cycle, date of last treatment.)

.mg

mg/m2

mg/m2

mg/m2

mg

mg

mg

.mg

mg.mg

mg/m2

mg/m2

mg/m2

mg

mg/m2

8053


11/15/2010

Page 2 of 2

IF DOSE MODIFICATIONS, COMPLETE THE FOLLOWING:

SWOG Patient ID SWOG Study No. S 0 8 0 6 Registration Step 1

Cycle Number:Patient Initials

Comments:

Rituximab

SAHA (Vorinostat)

Cyclophosphamide

Doxorubicin

Vincristine

Prednisone

Agent NameNumber of days delayed(if applicable)

Modification due toAdverse Event *(list all codes that apply)Dose Modification Reason

§

, ,

, ,

11 = Pulmonary/Upper Respiratory12 = Renal/Genitourinary13 = Vascular14 = Other, specify:

* Modification due to AE codes (if applicable) 1 = Allergy/immunology 2 = Blood/Bone Marrow 3 = Cardiac 4 = Coagulation 5 = Gastrointestinal 6 = Hepatobiliary/Pancreas 7 = Infection 8 = Metabolic/Laboratory 9 = Neurology10 = Pain

§ Agent Dose Modification Reasons (if applicable)1 = Adverse event2 = Patient refusal/non-compliance

(not due to toxicity)3 = Scheduling4 = Dosing error5 = Alternative therapy for other

reasons6 = Disease progression7 = Death8 = Other, specify:

, ,

, ,

, ,

, ,

8053

SOUTHWEST ONCOLOGY GROUPS0806 ADVERSE EVENT FORM

(L, F M)

11/15/2010

Page 1 of 2


SWOG Patient ID

Patient Initials


(L, F M)

Anemia

Febrile neutropenia


Constipation

Diarrhea

Dry mouth

Nausea

Vomiting

Chills

Edema face

Edema limbs

Edema trunk

Fatigue

Fever

Localized edema

Allergic reaction

Lung infection

Activated partial thromboplastintime prolongedAlanine aminotransferase

increasedAspartate aminotransferaseincreasedBlood bilirubin increased





Weight loss


Anorexia

Dehydration

Hyperglycemia

Hypoglycemia

Hyponatremia

CTC Adverse Event Term CTC Adverse Event Term

CTC Adverse

Event

Attribution

Code*

AdverseEventStatusCode**

CTC Adverse

Event

AttributionCode*

* Attribution codes: 1-unrelated 2-unlikely 3-possible 4-probable 5-definite

**Status codes (since baseline or last cycle): 1-new 2-continues at same or lower grade 3-increased grade OR improved then worsened

AdverseEventStatusCode**

11/15/2010



(Day 1 of this Cycle)

(Day one of next cycle. If final cycle,date of first visit or contact afterresolution of acute adverse events.)

ADVERSE EVENTS

CTCAE (4.0)

Grade(1 - 5)

CTCAE (4.0)

Grade(1 - 5)

Page 1 of 2

No Yes, but no reportable adverse events occurred

Yes, and reportable adverse events occurred (report below)

Were adverse events assessed during this time period?

Current Cycle Number:



Instructions: For patients on the Phase II portion, please complete and submit this form at the end of every cycle (1 cycle = 21days). Report adverse events occurring up until the next cycle of treatment begins. Document the worst Grade seen during thereporting period. Do not code a condition existing prior to registration as an adverse event unless it worsens. Category lists may notinclude all adverse events from that category. Record any observed adverse events not listed on the blank lines at the end. Alldates are MONTH, DAY, YEAR. Explain any blank dates or fields in the Comments section. Place an X in appropriate boxes.Circle AMENDED items in red and write AMENDED across top of form.

SWOG Patient ID

Patient Initials Current Cycle Number:

12947


(L, F M)

11/15/2010

Page 2 of 2

Genital edema

Cough

Dyspnea

Hypoxia

Alopecia

Hyperhidrosis

Rash maculo-papular

Hypertension

Hypotension


Hypophosphatemia


Arthralgia

Bone pain



Myalgia

Dizziness

Dysgeusia

Headache




Insomnia

Acute kidney injury

Urinary frequency



ADVERSE EVENTS, continued


Comments:

CTC Adverse Event Term

CTCAE (4.0)

Grade(1 - 5)

CTC Adverse

Event

AttributionCode*

AdverseEvent

StatusCode** CTC Adverse Event Term

CTCAE (4.0)

Grade(1 - 5)

CTC Adverse

Event

AttributionCode*

AdverseEvent

StatusCode**

CTC Adverse Event Term, Other(specify using CTCAE 4.0 terminology)

SWOG Patient ID

Patient Initials Current Cycle Number:

12947

SOUTHWEST ONCOLOGY GROUPS0806 DOSE-LIMITING TOXICITY RAPID REPORTING FORM

(L, F M)

11/15/2010

Page 1 of 2 SOUTHWEST ONCOLOGY GROUP

S0806 DOSE-LIMITING TOXICITY RAPID REPORTING FORM

SWOG Patient ID

Study WeekPatient Initials (L, F M)

11/15/2010

(see instructions)

Page 1 of 2






Anemia

Febrile neutropenia


Constipation

Diarrhea

Dry mouth

Nausea

Vomiting

Chills

Edema face

Edema limbs

Edema trunk

Fatigue

Fever

Localized edema

Allergic reaction

Lung infection

Activated partial thromboplastintime prolonged

Alanine aminotransferaseincreasedAspartate aminotransferaseincreasedBlood bilirubin increased





Weight loss


Anorexia

Dehydration

Hyperglycemia

CTC Adverse Event Term CTC Adverse Event Term

CTC Adverse

Event

AttributionCode*

Adverse

EventStatusCode**

CTC Adverse

Event

AttributionCode*

Adverse

EventStatusCode**



(Day 1 of this study week)

(Day one of next study week. If finalstudy week, date of first visit or

contact after resolution of acuteadverse events.)

ADVERSE EVENTS

CTCAE (4.0)

Grade(1 - 5)

CTCAE (4.0)

Grade(1 - 5)

No Yes, but no reportable adverse events occurred

Yes, and reportable adverse events occurred (report below)

Were adverse events assessed during this time period?

Instructions: For patients on the Phase I portion, please complete this form after each weekly toxicity assessment following the

initiation of protocol treatment. This form (like all forms for this study) must be submitted on-line. Do not fax or mail. A studyweek = 7 consecutive calendar days. Number weeks consecutively with Week 1 corresponding to the beginning of protocoltreatment. All of the adverse events listed below must be assessed and reported weekly. Document the worst Grade seen duringthe reporting period. Do not code a condition existing prior to initiation of protocol treatment as an adverse event unless it worsens.Category lists may not include all adverse events from that category. Record any observed adverse events not listed on the blanklines at the end. All dates are MONTH, DAY, YEAR. Explain any blank dates or fields in the Comments section. Place an X in

appropriate boxes. Circle AMENDED items in red and write AMENDED across top of form.

Date of Most Recent Adverse Event Assessment: / /

SWOG Patient ID

Study WeekPatient Initials

37980

SOUTHWEST ONCOLOGY GROUPS0806 DOSE-LIMITING TOXICITY RAPID REPORTING FORM

(L, F M)

11/15/2010

Page 2 of 2

Acute kidney injury

Urinary frequency

Genital edema

Cough

Dyspnea

Hypoxia

Alopecia

Hyperhidrosis

Rash maculo-papular

Hypertension

Hypotension


Hypoglycemia

Hyponatremia

Hypophosphatemia


Arthralgia

Bone pain



Myalgia

Dizziness

Dysgeusia

Headache




Insomnia



ADVERSE EVENTS, continued

Comments:


CTC Adverse Event Term

CTCAE (4.0)

Grade

(1 - 5)

CTC Adverse

Event

AttributionCode*

AdverseEvent

StatusCode** CTC Adverse Event Term

CTCAE (4.0)

Grade

(1 - 5)

CTC Adverse

Event

AttributionCode*

AdverseEvent

StatusCode**

CTC Adverse Event Term, Other

(specify using CTCAE 4.0 terminology)

SWOG Patient ID

Study WeekPatient Initials

37980

SOUTHWEST ONCOLOGY GROUPLYMPHOMA BASELINE TUMOR ASSESSMENT FORM

7/1/2009

Page 1 of 2


Instructions: Record the requested information for all measurable lesions and all sites of non-measurable disease, including sitesvisualized only by PET scan. Please refer to Section 10.1 of the protocol for definitions. If an organ or site has too manymeasurable lesions to measure at each evaluation, choose three to follow as measurable disease and record the rest asevaluable disease. Circle AMENDED items in red and write AMENDED across the top of the form.The same test procedures used for baseline disease assessment must be used for all required subsequent disease assessments.


7/1/2009

Page 1 of 2


Participating Group: Group Name/Study No./Patient ID / /



SWOG Patient ID SWOG Study No. S Registration Step

(CORETB_BTA)

Sites

L1

L2

L3

L4

L5

L6

SITES OF MEASURABLE LESIONS

SITES OF NON-MEASURABLE DISEASE

Extent

Sites Visualized Only by PET Scan Date of Assessment

/ // // // // /

P1

P2

P3

P4

P5

Other Sites of Disease

AssessmentCode* Date of Assessment

/ // // // // /

05-Endoscopy10-Plain film/X-ray without contrast11-Plain film/X-ray with contrast12-CT scan13-MRI scan

14-Radioisotope scan15-Ultrasound17-Spiral CT scan20-Histologic confirmation21-Cytologic confirmation23-PET/Spiral CT24-PET/Conventional CT

01-Palpation02-Visualization03-Colposcopy04-CA-125 assay

* Assessment Codes: 99-Other (specify below and indicate lesion number)

** PET Status: 0-Negative 1-Positive 8-Not applicable 9-Not imaged by PET

PETStatus **

PETStatus **

S1

S2

S3

S4

S5

Tumor Measurement (cm)


x

x

x

x

x

x / // // // // // /

.

.

.

.

.

.

.

.

.

.

.

.


48031


7/1/2009

Page 2 of 2


Comments:

List all negative diagnostic tests/studies used to evaluate patient for malignancy.

Tests/studies Date

/ // /

Tests/studies Date

/ // /


48031

SOUTHWEST ONCOLOGY GROUPLYMPHOMA FOLLOW-UP TUMOR ASSESSMENT FORM

7/1/2009

Page 1 of 2



7/1/2009(CORETB_FUTA)

Page 1 of 2

Instructions: Record the requested information for all measurable lesions and all sites of non-measurable disease, including sitesvisualized only by PET scan. Please refer to Section 10.1 of the protocol for definitions. If an organ or site has too manymeasurable lesions to measure at each evaluation, choose three to follow as measurable disease and record the rest asevaluable disease. Circle AMENDED items in red and write AMENDED across the top of the form.The same test procedures used for baseline disease assessment must be used for all required subsequent disease assessments.





Reporting Period Start Date: / /

Sites

L1

L2

L3

L4

L5

L6

SITES OF MEASURABLE LESIONS

SITES OF NON-MEASURABLE DISEASE

Extent

Sites Visualized Only by PET Scan Date of Assessment

/ // // // // /

P1

P2

P3

P4

P5

Tumor Measurement (cm)


x

x

x

x

x

x / // // // // // /

.

.

.

.

.

.

.

.

.

.

.

.

Other Sites of Disease

S1

S2

S3

S4

S5


/ // // // // /

PETStatus **

PETStatus **

** PET Status: 0-Negative 1-Positive 8-Not applicable 9-Not imaged by PET

05-Endoscopy10-Plain film/X-ray without contrast11-Plain film/X-ray with contrast12-CT scan13-MRI scan

14-Radioisotope scan15-Ultrasound17-Spiral CT scan20-Histologic confirmation21-Cytologic confirmation23-PET/Spiral CT24-PET/Conventional CT

01-Palpation02-Visualization03-Colposcopy04-CA-125 assay

* Assessment Codes: 99-Other (specify below and indicate lesion number)



64395


7/1/2009

Page 2 of 2


List all negative diagnostic tests/studies used to evaluate patient for malignancy.

Tests/studies Date

/ // /

Tests/studies Date

/ // /

Comments:



64395

Has the patient had a documented clinical assessment for this cancer (since submission of the previous follow-up form)?

No Yes

Instructions: Please submit at each follow up after completion of treatment until relapse or progression, at time of relapse orprogression, and at protocol-specified intervals after relapse or progression. Also submit at time of diagnosis of second primary.All dates are MONTH, DAY, YEAR. Answer all questions and explain any blank fields or blank dates in the Comments section.Place an X in appropriate boxes. Circle AMENDED items in red.

SOUTHWEST ONCOLOGY GROUP FOLLOW UP FORM

9/15/2003

Comments:

NON-PROTOCOL TREATMENT

NOTICE OF FIRST RELAPSE OR PROGRESSION

NOTICE OF NEW PRIMARY

DISEASE FOLLOW UP STATUS

VITAL STATUS

No Yes If Yes, Date of Diagnosis: / /Has a new primary cancer or MDS (myelodysplastic syndrome) been diagnosed that has not been previously reported?

New Primary Site:

Has the patient developed a first relapse or progression that has not been previously reported?

No Yes If Yes, Date of Relapse or Progression: / /

Site(s) of Relapse or Progression:

Has the patient received any non-protocol cancer therapy (prior to progression/relapse) not previously reported?

No Yes If Yes, Date of First Non-Protocol Therapy: / /Agent Name(s):

Has the patient experienced (prior to treatment for progression or relapse or a second primary, and prior tonon-protocol treatment) any severe (grade 3) long term toxicity that has not been previously reported?

If Yes, Adverse Events and Grades:

No Yes




Date of last contact or death: / /Vital Status: Alive DeadIf vital status is Dead, complete and submit Notice of Death form.

If Yes, Date of Last Clinical Assessment: / /

Page 1 of 1

LONG TERM ADVERSE EVENT


64587

Instructions: Report any malignancy of a new histologic type or any malignancy of a previous type which is judged to be anew primary. Do not report recurrences on this form. Note: If available, submit pathology report documenting the secondmalignancy along with this form. Refer to the protocol regarding sample submission instructions for second malignancies.All dates are MONTH, DAY, YEAR. Circle AMENDED items in red.

SOUTHWEST ONCOLOGY GROUPNOTICE OF SECOND MALIGNANCY

10/15/2000

Notes:

Page 1 of 1

(PRIM2)

Protocol Step 1SWOG Study No. SSWOG Patient No.

Date of First Pathologic Diagnosis:

/ /

Type (site, histology) of second malignancy:

Patient Initials (L, F, M)

Groups Other than SWOG: Group Name/Study No./Pt. No.

PhysicianInstitution/Member

//

27456

6/1/2010Comments:

SOUTHWEST ONCOLOGY GROUPOFF TREATMENT NOTICE



(If more room is needed, please continue on a separate page)


Page 1 of 1


Systemic Therapy: List regimens, start and end dates. For multidrug regimens, do not list individual drugs separately;end date would be the date all drugs in the regimen were discontinued.

Surgery: List type of surgery, and in the "end date" column, the date of surgery.

Radiation: List sites, start and end dates (inclusive of boosts and implants).

Instructions: For each registration step, submit this form within 2 weeks after completion (or discontinuation) of treatment.List protocol-directed treatments that the patient received.

All dates are MONTH, DAY, YEAR. Explain any blank fields or blank dates in the Comments section.Place an X in appropriate boxes. Circle AMENDED items in red and write AMENDED at the top of the form.

For any patient refusal, was reason due to adverse event/side effects/complications?

Yes, specify:

No, specify other reason for refusal:

Off Treatment Reason

Treatment completed per protocol criteria

Adverse event/side effects/complications, specify:

Patient withdrawal/refusal after beginning protocol therapy, specify:

Patient withdrawal/refusal prior to beginning protocol therapy, specify:

Disease progression, relapse during active treatment; Sites:

Death on study (submit Notice of Death form)

Other, specify:

(select one):

For any adverse event, was treatment termination medically required?

No Yes, specify:

Treatment Start Date Treatment End Date Regimen or Procedure or Site(s)

/ /

/ /

/ /

/ /

/ /

/ /

/ /

/ /

/ /

/ /

Off Treatment Date

Date of completion, progression, death or decision to discontinue therapy: / /

Will patient receive further treatment?

No Yes, specify: Unknown

Date of Last Contact or Death: / /Vital Status: Alive Dead (submit Notice of Death form)

Did the patient receive any protocol treatment (on this registration step)? Yes No

52393

9/1/2003

Comments:

SOUTHWEST ONCOLOGY GROUPNOTICE OF DEATH

Autopsy? No Yes Unknown

If cancer was the primary cause or if cancer possibly or definitely contributed to death, and the patienthad had multiple tumor types, specify those which were causes of death:

No Primary Cause Contributory Possible UnknownAny cancer (select one):

CAUSES OF DEATH

(month / day / year)Date of Death: / /

SWOG Patient ID Most Recent SWOG Study No. S



Cancer of most recent SWOG study, specify cancer:

Cancer of other SWOG study, specify cancer:

Other cancer, specify:

If Primary Cause, Contributory or Possible, specify treatment and toxicity:

No Primary Cause Contributory Possible UnknownToxicity from disease related treatment (select one):

If Primary Cause, Contributory or Possible, specify:

No Primary Cause Contributory Possible UnknownNon-cancer and non-treatment related causes (select one):

Source(s) of death information:

Autopsy report

Medical record / Death certificate

Physician

Relative or friend

Other, specify:

Instructions: Answer all questions and explain any blank fields or blank dates in the Comments section.Place an X in appropriate boxes. Circle AMENDED items in red.


Page 1 of 1

49467

S0806 Page 96

19.0 APPENDIX 19.1 Determination of Expedited Adverse Event Reporting Requirements 19.2 Intake Calendar

S0806 Page 97

19.1 Determination of Expedited Adverse Event Reporting Requirements Adverse event data collection and reporting, which are required as part of every clinical trial, are done to ensure the safety of patients enrolled in the studies as well as those who will enroll in future studies using similar agents. Adverse events are reported in a routine manner at scheduled times during a trial. (Directions for routine reporting are provided in Section 14.0.) Additionally, certain adverse events must be reported in an expedited manner to allow for more timely monitoring of patient safety and care. Expedited adverse event reporting principles and general guidelines follow; specific guidelines for expedited adverse event reporting on this protocol are found in Section 16.0. All serious adverse events must also be reported to the local Institutional Review Board (IRB). Documentation of this reporting should be maintained for possible inspection during quality assurance audits. Reporting requirements may include the following considerations: 1) whether the patient has received an investigational or commercial agent; 2) the characteristics of the adverse event including the grade (severity), the relationship to the study therapy (attribution), and the prior experience (expectedness) of the adverse event; 3) the Phase (1, 2, or 3) of the trial; and 4) whether or not hospitalization or prolongation of hospitalization was associated with the event. An investigational agent is a protocol drug administered under an Investigational New Drug Submission (IND). In some instances, the investigational agent may be available commercially, but is actually being tested for indications not included in the approved package label. Commercial agents are those agents not provided under an IND but obtained instead from a commercial source. The NCI, rather than a commercial distributor, may on some occasions distribute commercial agents for a trial. When a study includes both investigational and commercial agents, the following rules apply.

• Concurrent administration: When an investigational agent(s) is used in combination with a commercial agent(s), the combination is considered to be investigational and expedited reporting of adverse events would follow the guidelines for investigational agents.

• Sequential administration: When a study includes an investigational agent(s) and a commercial agent(s) on the same study arm, but the commercial agent(s) is given for a period of time prior to starting the investigational agent(s), expedited reporting of adverse events that occur prior to starting the investigational agent(s) would follow the guidelines for commercial agents. Once therapy with the investigational agent(s) is initiated, all expedited reporting of adverse events should follow the investigational guidelines.

Steps to determine if an adverse event is to be reported in an expedited manner Step 1: Identify the type of event using the NCI Common Terminology Criteria for Adverse Events (CTCAE). The CTCAE provides descriptive terminology and a grading scale for each adverse event listed. A copy of the CTCAE can be downloaded from the CTEP home page (http://ctep.cancer.gov). Additionally, if assistance is needed, the NCI has an Index to the CTCAE that provides help for classifying and locating terms. All appropriate treatment locations should have access to a copy of the CTCAE.

S0806 Page 98

Step 2: Grade the event using the NCI CTCAE version specified. Step 3: Determine whether the adverse event is related to the protocol therapy (investigational or commercial). Attribution categories are as follows: Unrelated, Unlikely, Possible, Probable, and Definite.

Step 4: Determine the prior experience of the adverse event. Expected events are those that have been previously identified as resulting from administration of the agent. An adverse event is considered unexpected, for expedited reporting purposes only, when either the type of event or the severity of the event is not listed in

• the current NCI Agent-Specific Adverse Event List (for treatments using agents provided under an NCI-held IND);

• the drug package insert (for treatments with commercial agents only); • Section 3.0 of this protocol.

Step 5: Review Tables 16.1 and 16.2 in the protocol to determine if there are any protocol-specific requirements for expedited reporting of specific adverse events that require special monitoring. Step 6: Determine if the protocol treatment given prior to the adverse event included an investigational agent(s), a commercial agent(s), or a combination of investigational and commercial agents. NOTE: This includes all events that occur within 30 days of the last dose of protocol treatment. Any event that occurs more than 30 days after the last dose of treatment and is attributed possibly, probably, or definitely to the agent(s) must be reported according to the instructions in Table 16.1 or 16.2.

SOUTHWEST ONCOLOGY GROUP INTAKE CALENDAR

SWOG Study No. SSWOG Patient ID Registration Step

9/15/2004

Special instructions:


Month: Year:

Sunday Monday Tuesday Wednesday Thursday Friday Saturday

Instructions for the Nurse or Research Coordinator:Give this intake calendar to the participant for her use with contact information filled in. Instruct the participant to bring her intake calendar to each visit.

This form does not need to be returned to the Data Operations Center.

Patient Initials (L, F, M)

Page 1 of 1

If you have any questions contact: Telephone:

Your next appointment is:

Instructions for the participant:This is a monthly calendar on which you are to record the number of tablets you take each day. Be sure you haveenough calendars to last until your next appointment. If you develop any side effects from the tablets, mark this onthe calendar on the day you note the effect. Bring your calendars with you each time you have an appointment.


30471