Blood and Marrow Transplant Clinical Trials Network (BMT CTN):

Past, Present and FutureHillard M. Lazarus, MD

The George & Edith Richman Professor and Distinguished Scientist in Cancer Research

Director of Novel Cell TherapyUniversity Hospitals Case Medical Center

Case Western Reserve University

E Donnall Thomas, MD 1920-2012Nobel Prize in Physiology or Medicine, 1990

• N=6 pts: variety of diseases, malignant & non-malignant• differing marrow products infused• demonstrated safety (no marrow emboli)• demonstrated some donor engraftment

ED Thomas, et al. N Engl J Med 257: 491-496, 1957

BONE MARROW TRANSPLANTATIONInitial Report: Mary Imogene Bassett Hospital

F Appelbaum. N Engl J Med 357: 1472-1475, 2007

Genesis

I can’t cover everything

BLOOD AND MARROW TRANSPLANT CLINICAL TRIALS NETWORK

Established November 2001 Mission: Conduct scientifically meritorious

multicenter trials in an efficient manner to improve transplant outcomes

Provide infrastructure to allow promising therapies to be developed/evaluated in high quality, multicenter studies that give definitive answers as rapidly as possible

NHLBI & NCI

STEERING COMMITTEE

AdministrativeCommittees

TechnicalCommittees

Data and Coordinating Center

BMT03new_2.ppt

Protocol Teams

Affiliate Clinical Centers

20 Clinical Cores; High-performing Affiliate Centers

NCI Coop Group Chairs (ex officio)

Protocol ReviewCommittee

Data and SafetyMonitoring Board

BMT CTN Organizational Structure

NMDPPatient Advocacy

Contracting

Overall Coordination

Statistical Design/Analysis

Protocol Development/

Implementation

Scientific Leadership

Medical Monitoring

* EMMESTrial Oversight/

Monitoring

Lab/Repository

Management

ElectronicCommunications

DataManagement

BMT CTNData and Coordinating Center

CIBMTR

* professional partner to clinicians, scientists, program leaders

BLOOD & MARROW TRANSPLANTATION1st State of Science Symposium: 4/01/2000

• Stem cell source & donor selection – Horowitz, Champlin, Anasetti, Hansen, Wagner, Confer

• Regimen-related toxicity – Armitage, Blume, McDonald, Jones

• Graft-versus-host disease – Blazar, Martin, Guinan, Parkman, Storb, Ferrara

• Recurrence after autograft – Nadler, Vose, Press, Gribben, Antman

BLOOD & MARROW TRANSPLANTATION1st State of Science Symposium: 4/01/2000

• Recurrence after allograft – O’Reilly, Scheinberg, Barrett, Levitsky, Riddell

• Infectious complications – Wingard, Forman, Zaia, Heslop

• Late complications & immune recovery – Sullivan, Weinberg, Gress, Vogelsang

BLOOD & MARROW TRANSPLANTATION1st State of Science Symposium

Conclusions:

1. Necessity of multi-institutional studies

2. Studies can be adapted to multi-institutional setting

3. Studies could be completed in a responsible time

Conclusions for studies needed:

1. Blood vs marrow in matched sibling donors – (NA)2. Blood vs marrow in matched unrelated donors – (0201)3. Techniques to improve cord blood engraftment – (0501)4. T-cell depletion studies – (0303) 5. Methods to improve autologous cell collection – (NA)6. Comparisons of related and unrelated HCT vs standard chemotherapy for high risk patients – (S1203)

BLOOD & MARROW TRANSPLANTATION1st State of Science Symposium

RFA from NHLBI in 2001 Competition for Data Coordinating Center (DCC)

Emmes Corp, NMDP and CIBMTR awarded

Competition for Centers Established 16 Core Centers Case Consortium original Core Center

( Re-competition: expanded to 20 in July 2011 )

BMT CTN FOUNDATION Creation and Organization/Administration

Case Western Reserve University (CWRU); Oregon Health Sciences University (OHSU); University of Illinois Chicago

Transition to add Washington University (St. Louis) and Ohio State University (through 2011)

Present configuration CWRU, OHSU Cleveland Clinic, West Virginia University

BMT CTN Case Consortium (Original & Current)

Formation of committees and teams: Manual of Policies/Procedures (MOP) Disease-specific teams Protocol-specific teams Liaison relation with cooperative oncology groups Electronic data capture system Per patient reimbursement model Websites for members & public Metrics for center performance: “Report Card”

BMT CTN FOUNDATION Creation and Organization/Administration

Protocol Development & Prioritization

Feasibility Issues

Scientific Rationale

Logistical/ budgetary

Constraints

Clinical Population

No. pts 440 1,058 1,615 2,133 2625 3048 4,200 5,200

Collaboration with cooperative groups to avoid duplication

C

= Enrollment complete

= Enrollment on-going

= Cumulative actual [projected] accrual

= Coop group collaboration(see color key above)

2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013

0101 PIII Vori vs. Fluconazole0201 PIII Unrelated PBSC vs. Marrow

0102 PIII Myeloma Tandem HCT

0202 PIII follicular NHL (closed early)

0301 PII Unrelated Tx for aplastic anemia

0302 PII AGVHD therapy0303 PII T-depleted HCT for AML

0401 PIII BEAM vs BEAM-Bexxar for Lymphoma

0402 PIII GVHD prophylaxis

0403 PIII Etanercept for IPS (closed early)

0501 III Single vs Double CBT

0502 PII NST for AML >60y

0601 PII Sickle Cell NST0603 PII Haplo in Adult

0604 PII DCB in Adult

0701 PII NST for NHL

0702 PIII Myeloma Follow-on

0703 PII HD

0704 PIII MM maintenance

0801 P II/III CGVHD Treatment0802 PIII AGVHD Treatment

0803 HIV+ Lymphoma

0804 High Risk CLL0901 Full vs RIC - MDS/AML

0902 Post Tx Stress Mgmt

0903 Allo Tx for HIV+1101 Haplo vs. 2 UCB

Mmh11_9.ppt

BMT CTN Centers, 2013>115 centers enrolled >5000 pts since 2003

= Core Centers = PBMTC Centers = Affiliate Centers

BMT CTN: Numbers of Protocols Opened

2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 (proj)

0

1

2

3

4

5

6

7

8

02010202

01010102

030203030401

030104020501

04030502*0704*

0601060306040703*

0701

0702 08030801 0804*0802 0805*

09010902

09031101

11021202120312041205

BMT CTN Yearly & Cumulative Accrual All Protocols, 2004-2012

BMT CTN TRIALS Protocol Categories

All Trials Phase II Phase IIIDonor/Graft Source 12 6 6GVHD 5 3 2Infection 3 2 1Disease Control 12 6 6Regimen Toxicity 4 2 2QOL 7 2 5TOTAL 28 14 14

BMT CTN Publications Summary

2012: 7 peer-reviewed papers (+1 in press)

28 total: 10 primary results papers: 0101, 0102,

0202, 0301, 0302, 0303, 0401, 0601, 0603/0604, 0704 (100104)

8 other protocol-related papers 3 methodology papers 7 other Network publications

BLOOD & MARROW TRANSPLANTATION2nd State of Science Symposium

- BMT CTN organized and led- June 7-8, 2007 @ Ann Arbor, MI- Goal: identify key transplant-related issues- Propose critical trials to address these issues

- may be sequential phase II III- may require cooperative oncology group or

other participants- trials should be ready to start quickly

BLOOD & MARROW TRANSPLANTATION2nd State of Science Symposium

1. Optimal donor and graft source – C. Anasetti

2. Regimen-related toxicity – E. Stadtmauer

3. Graft-versus-host disease – J. Antin

4. Infection & immune reconstitution – J. Wingard

5. Late effects/quality of life – S. Lee

6. Pediatrics – K. Schultze, J. Levine

BLOOD & MARROW TRANSPLANTATION2nd State of Science Symposium (con’t)

7. Leukemia – F. Appelbaum

8. Lymphoma – R. Negrin

9. Plasma cell myeloma – S. Giralt

10. Non-malignant disorders – C. Bredson

11. Gene and cell therapy – H. Heslop, D. Kohn

12. Cinical trial design – M. Horowitz

April 2006 Committees named and chargedJune-Dec 2006 Committee conference callsDec 2006 Committee in-person mtgs @ ASHFeb 2007 Committee in-person mtg @ TandemMay 2007 Document dueJune 2007 SOSS

JL Ferrara, BMT CTN. Biol Blood Marrow Transplant 13: 1268-1285, 2007

BLOOD & MARROW TRANSPLANTATIONTimeline: 2nd State of Science Symposium

1. GVHD: Phase II trial calcineurin-free regimen – 0402

2. QOL: Phase III study stress management – 0902 3. Myeloma: Phase III comparison tandem HCT vs. consolidation and maintenance – 0702

4. AML: Phase III chemotherapy vs. URD HCT – SWOG 1203

5. AML: Phase III full intensity vs. RIC HCT - 0901

6. Ph+ ALL: Phase III chemotherapy vs. Allo HCT – S0805

BLOOD & MARROW TRANSPLANTATION2nd State of Science Symposium: Conclusions

7. CLL: Phase II RIC Allo HCT for high risk CLL – 0804

8. Lymphoma: Phase II RIC Allo HCT in T cell lymphoma – NA

9. HLH: Phase II RIC for children with HLH – planning

10. Non-malignant: Phase II auto HCT in Crohn disease – NA

11. Cell Therapy: Phase II viral-specific CTL adenovirus - NA

BLOOD & MARROW TRANSPLANTATION2nd State of Science Symposium: Conclusions

MAJOR SCIENTIFIC PUBLICATIONSPotentially Practice-Changing

BMT CTNDonor Graft Source Questions

Blood versus Marrow

Extremely complex undertaking;Dual consent: donor and recipient

C Anasetti, BMT CTN. N Engl J Med 367: 1487-96, 2012.

BLOOD vs MARROW GRAFT SOURCEMatched Unrelated Donors (MUD): Engraftment

C Anasetti, BMT CTN. N Engl J Med 367: 1487-96, 2012.

BLOOD vs MARROW GRAFT SOURCEMatched Unrelated Donors (MUD): GVHD

C Anasetti, BMT CTN. N Engl J Med 367: 1487-96, 2012.

BLOOD vs MARROW GRAFT SOURCEMatched Unrelated Donors (MUD): Relapse & TRM

C Anasetti, BMT CTN. N Engl J Med 367: 1487-96, 2012.

BLOOD vs MARROW GRAFT SOURCEMatched Unrelated Donors (MUD): Survival

BMT CTN 0401Reduce Relapse After Autograft: NHL

DLBCL: BEXXAR-BEAM vs Rituximab-BEAM

No differences in patient outcome except increased mucositis

Randomized to Bexxar/BEAM or Rituxan/BEAM

Day -19

Day -12

Day -6Days -5 to -2Days -5 to -2Day -1

Day 0

Bexxar 75 cGy TBD

Bexxar 5 mCi Rituxan 375 mg/m2

Rituxan 375 mg/m2

Infusion of mobilized hematopoietic cells

BCNU 300 mg/m2

Etoposide [VP-16] 100 mg/m2 BID (8 doses)Ara-C [Cytarabine] 100 mg/m2 BID (8 doses)Melphalan 140 mg/m2

Day +5 G-CSF 5 µg/kg daily until ANC >500/mm3 x 3 days

Within 3 mo of mobilization

dosimetry

Prob

abili

ty, %

Months0 12 24 48

100

0

20

40

60

80

90

10

30

50

70

0

100

20

40

60

80

90

10

30

50

70

6 18 30 36 42

Rituxan/BEAM (N=113)

Bexxar/BEAM (N=111)

Bexxar/BEAM @ 2 yr: 48.6% p=0.65Rituxan/BEAM @ 2 yr: 49.0%

BMT CTN 0401Autograft BEXXAR-BEAM vs Rituximab-BEAM

Probability Progression-free survival (PFS)

JM Vose, BMT CTN. J Clin Oncol 31: 1662-1668, 2013.

Prob

abili

ty, %

Months0 12 24 48

100

0

20

40

60

80

90

10

30

50

70

0

100

20

40

60

80

90

10

30

50

70

6 18 30 36 42

Rituxan/BEAM (N=113)

Bexxar/BEAM (N=111)

Bexxar/BEAM @ 2 yrs: 60.1% p=0.29Rituxan/BEAM @ 2 yrs: 66.3%

BMT CTN 0401Autograft BEXXAR-BEAM vs Rituximab-BEAM

Probability Survival

JM Vose, BMT CTN. J Clin Oncol 31: 1662-1668, 2013.

BMT CTNRelapse Prevention Questions: Myeloma

Tandem Autograft vs Autograft-Allograft

A Krishnan, BMT CTN. Lancet Oncol 12: 1195-203, 2011.

TRANSPLANTATION IN MYELOMATandem Autograft vs Autograft-RIC Allograft

Autografts: Melphalan 200 mg/m2

Allograft: TBI 200 cGy

A Krishnan, BMT CTN. Lancet Oncol 12: 1195-203, 2011.

TRANSPLANTATION IN MYELOMATandem Autograft vs Autograft-RIC Allograft

Standard-risk

A Krishnan, BMT CTN. Lancet Oncol 12: 1195-203, 2011.

TRANSPLANTATION IN MYELOMATandem Autograft vs Autograft-RIC Allograft

High-risk

BMT CTNRelapse Prevention Questions: Myeloma

Post-Autograft Maintenance Therapy

AUTOGRAFT IN MYELOMAPost-Transplant Lenalidomide vs Placebo

PL McCarthy, BMT CTN. N Engl J Med 366: 1770-81, 2012.

Joint BMT CTN and CALGB study

Median TTP 46 mo

Median TTP 27 mo

88% @ 3 yr

80% @ 3 yr

AUTOGRAFT IN MYELOMAPost-Transplant Lenalidomide vs Placebo

PL McCarthy, BMT CTN. N Engl J Med 366: 1770-81, 2012.

Risk 2nd maligancy

BMT CTNNovel GVHD Prevention Strategies

T Cell Depletion and Other Strategies

HEMATOPOIETIC CELL TRANSPLANTAllograft & High-dose Rituximab in FCC NHL

IF Khouri, MD Anderson. Blood 111: 5530-5536, 2008

Survival

Graft-vs-Host Disease

BMT CTN 0701Allograft & High-dose Rituximab in FCC NHL

Rituximab 375 mg/m2 (day –13)Rituximab 1,000 mg/m2 (day – 6)

Fludarabine + Cyclophosphamide conditioning

Tacrolimus+ Methotrexate (GVHD prophylaxis)

Rituximab 1,000 mg/m2 day +1 and +8Blood allograft infusion (matched-related or MUD)

PK studies for rituximab blood concentration

Accrual completed: awaiting DSMB recommendations

GRAFT-VS-HOST DISEASEProphylaxis: T Cell Depletion

• Decades of failure• Engraftment failure• Prolonged immune incompetence• viral, opportunistic infections

• High relapse rates

VT Ho, RJ Soiffer. Blood 98: 3192-204, 2001.

GRAFT-VS-HOST DISEASEProphylaxis: AML CR1 & T Cell Depletion

S Devine, BMT CTN. Biol Blood Marrow Transplant 17: 1343-51, 2010

• Multi-center BMT CTN trial: CD34 selection, Miltenyi device• Few AML CR2; early follow-up

Grade 3-4 Acute GVHD Chronic

GVHD

GRAFT-VS-HOST DISEASEProphylaxis: AML CR1 & T Cell Depletion

S Devine, BMT CTN. Biol Blood Marrow Transplant 17: 1343-51, 2010

Relapse

No engraftment failures

Survival

AML CR1 ALLOGRAFTS: BMT CTNT Cell Depletion vs Immune Suppression

MC Pasquini, BMT CTN. J Clin Oncol 30: 3194-3201, 2012

GVHD-Free Survival

Survival

N=44 T Cell Depletion; N=88 Immune Suppression

Relapse

GRAFT-VS-HOST DISEASEProphylaxis: Combination

C Cutler, BMT CTN. Blood 120: 2012 (abstract #739).

Myeloablative conditioning: Cy or VP-16 plus TBI > 1200 cGyMobilized blood graft Median (range) age 44 (13-59) yr

Sirolimus/tacrolimus:No advantage in 114-day acute GVHD-free survival• 2 and 3 days faster neutrophil and platelet engraftment• Reduction in acute GVHD

8% absolute II-IV, p = 0.17 7% absolute III-IV, p = 0.05

• More chronic GVHD 9% absolute , p = 0.05

• Less mucositis but more endothelial injury (all p 0.05)Acceptable alternative to tacrolimus/methotrexate

BMT CTN GVHD PROPHYLAXISSirolimus/Tacrolimus vs Tacrolimus/Methotrexate

BMT CTNRegimen-Intensity Questions

Acute Leukemia and MDS

ACUTE MYELOID LEUKEMIA CR1Reduced-Intensity Conditioning in Elderly

ACUTE MYELOID LEUKEMIA CR1Reduced-Intensity Conditioning in Elderly• CALGB & BMT CTN: N=123 @ 21 centers • Median age 65 (60-74) yr• N= 58 matched-related donor; N=65 MUD• 82 intermediate cytogenetics; 25 adverse cytogenetics• Fludarabine + busulfan ± ATG

SM Devine, CALGB, BMT CTN. Blood 120: 2012 (abstract #230).

Event Incidence @ 2 Yr

Treatment-related mortality

14%

Acute GVHD gr 3-4 3.4% @ 100 days

Chronic GVHD 26%Relapse 47%

Overall survival 46%

ACUTE MYELOID LEUKEMIA CR1Prospective Randomized: RIC vs Myeloablative

M Bornhäuser, German AML. Lancet Oncol 13: 1035-1044, 2012.

German AML Study Group: small series

ACUTE MYELOID LEUKEMIA & ALLOGRAFTMyeloablative vs Reduced-Intensity Conditioning

BMT CTN 0901

BMT CTNAlternative Donor Graft Source Questions

No Matched-Related or MUD Available

GRAFT-VS-HOST DISEASEPost-Transplant Cyclophosphamide

L Luznik, Hopkins. Blood 115: 3224-30, 2010.

N=117; Bu/CYT-replete marrowCY 50 mg/kg/d T+3, T+4

Chronic GVHD

Acute GVHD

BMT CTN Protocol 1101

Multi-center, Phase III, Randomized Trial of Reduced Intensity Conditioning and Transplantation

Of Double Unrelated Umbilical Cord Blood versusHLA-Haploidentical Related Bone Marrow for

Patients with Hematologic Malignancies

Followup to 2 independent BMT CTN phase II studies BMT CTN 0603 and 0604

45%31%

54%

CG Brunstein, BMT CTN. Blood 118:282-288, 2011

Patient ≥ 18 and ≤70 yrAcute leukemia or lymphoma

Adequate organ functionPerformance score ≥70

No sibling or matched unrelated donor available, BUT:• Double umbilical cord blood (UCB) graft • Haploidentical related donor marrow (Haplo-BM)• No donor specific anti-HLA-Ab

RandomizationStratified by Transplant Center

Double UCB

Haplo-BM

BMT CTNStudy Design Protocol 1101

BMT CTN Protocol 1101

Minnesota Protocol (0604)

Hopkins Protocol (0603)

Eliminate alloreactive T cells

Haploidentical

BMT CTN Manuscripts in Preparation

0402 – Sirolimus vs methotrexate (in combo with tacrolimus) to prevent acute GVHD : NO BENEFIT

0403 – Etanercept for Idiopathic Pneumonia Syndrome: NO BENEFIT

0501 – Single vs double UCB transplant in children: MORE GVHD with double; NO ADVANTAGE engraftment or survival

0502 – RIC HCT for older AML adults: GOOD RESULTS

0802 – MMF as initial therapy for AGVHD: NO BENEFIT

BMT CTN Future

• Continued accrual enhancement• Continued publications in high-impact journals• Repository trials: GVHD blood biomarkers

BMT CTN Protocol 1202

Prospective Multi-Center Cohort for the Evaluation of Biomarkers Predicting Risk of Complications and Mortality

Following Allogeneic HCT

1,500 allogeneic patients over 4 yr: HCT only @ US centers Samples collected for DNA, RNA, and proteins: R24Building upon University of Michigan data and other sourcesData collection for post-transplant complications

Biomarker Approach Sample No.

PtsPre-

ConditioningPre-HCTDay -1 or

0

Days post-HCT

7±2

14 ± 2

21 ± 2

28 ± 2

42 ± 3

56 ± 3

90±10

GeneticDNA17mL blood

1500 X

ProteomicSerum(10 mL blood)

1500 X X X X X X X X

Gene Expression

PAXgeneLysates-(20 mL blood)

240 X X

Recipient SamplesBMT CTN Protocol 1202

BMT CTN Future (con’t)

• Partnering with other groups:• IFM• Canadians• Germans

• Increased companion translational trials: obesity• 3rd State of the Science Symposium

IFM/DFCI 2009Phase III: Untreated Myeloma

Arm A RVD Cycles 2-3 HD Cytoxan; collect cells RVD Cycles 4-8 Maintenance lenalidomide(Melphalan + HCT @ relapse)

Arm B RVD Cycles 2-3 HD Cytoxan; collect cells HD Melphalan + HCT RVD for 2 more cycles Maintenance Lenalidomide

RANDOMIZE

• Symptomatic myeloma with measurable disease<65 yrs and transplant-eligible; ECOG <2 (KPS ≥60%)

1° Endpoint: PFS

2° Endpoints: relapse, TTP, survival, QOL, economics, genetic prognostic

Initial Therapy

RVD Cycle 1

RVD=lenalidomide; bortezomib; dexamethasone

BMT CTN Future (con’t)

• Partnering with other groups:• IFM• Canadians• Germans

• Increased companion translational trials: obesity• 3rd State of the Science Symposium

Myeloma patients within 9 months of diagnosis

Single autograft +/- consolidation versus tandem autograft and maintenance

N=750 patients (250 each arm)

Uniformity of treatment:

Melphalan 200 mg/m2 IV plus autograft

Accrual nearly reached

COOPERATIVE ONCOLOGY GROUPSObesity and Myeloma: BMT CTN 0702

Myeloma is an obesity-driven disease

Critical questions- What is impact of obesity on treatment and disease?

- If obesity has detrimental effects, what are the mechanisms & how can these be addressed & improved?

- If obesity has beneficial effects, how can these be identified and used to enhance therapeutic outcomes?

COOPERATIVE ONCOLOGY GROUPSCompanion Investigation: Example

OBESITY AND MYELOMA

Limitations of BMI (body mass index) Anthropomorphic measures of abdominal adiposity

correlate with cardiovascular and cancer mortality: independent of BMI

Which anthropomorphic measurements are better? Waist:Hip measure better indicator of visceral fat better correlation with incidence colon & ovarian cancer

C Zhang, et al. Circulation 117: 1658-1667, 2008YC Wang, et al. Obesity 15: 2855-2865, 2007

OBESITY AND MYELOMA

Opportunity to study prospectively other biologic measurements

Identify mechanisms by which obesity impacts therapy

Identify mechanisms by which obesity affects disease progression

Identification of potential markers and mediators to impact disease progression

Companion translational obesity study to transplant trial

Investigators:HM LazarusE CampagnaroNA Berger

Anthropomorphic measures at frequent intervalsAnalysis of prospectively collected/archived blood samples

COOPERATIVE ONCOLOGY GROUPSClinical Investigation: Example

Measure Hip & Waist Circumference

OBESITY AND TRANSPLANTMyeloma: BMT CTN 0702

Waist:Hip measurement

Plasma biomarkersAdipokines/cytokines:• adiponectin, leptin, IL-6, TNF-αHormones: • insulin, C-peptide, pancreatic peptide (PP), peptide YY (PYY)Growth factors: • IGF-1, IGFBP-3

BMT CTN Future (con’t)

• 3rd State of the Science Symposium• February 24-25, 2014 @ Grapevine, TX