patient diagnosis date - kimberly...

PATIENTpan-692_14051015.1516

DIAGNOSISPancreas ductal adenocarcinoma

DATE20 November 2015

Dr. __________,

Please see the enclosed molecular analysis for . Once you have had achance to review the Perthera Report, please provide feedback on the key points of information inthe short form on the following page and fax back to 888-965-8043.

We greatly appreciate your support.

Sincerely,

Michael Pishvaian, MD PhDChief Medical OfficerPerthera

This analysis was sponsored by: Pancreatic Cancer Action Network®

Confidential patient information – distribute in compliance with HIPAA requirements for PHI

Personalized Cancer Therapy, Inc.8200 Greensboro Dr, Suite 350, McLean, VA 22102

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PATIENT DIAGNOSISPancreas ductal adenocarcinoma


Perthera Report Feedback

Patient:

(1) What treatment were you planning (or have started) for this patient prior to receiving the Perthera Report?

(2) What will you now treat the patient with based on the Perthera Report?Immunotherapy plus irinotecan-based chemotherapy - NCT02423954 Study of Nivolumab PlusChemotherapy in Patients With Advanced Cancer (NivoPlus)

MM-398 plus 5FU or FOLFIRI

Capecitabine + ruxolitinib

A clinical trial of a MEK inhibitor combination or - e.g., NCT02022982 or NCT01449058 A Phase IbStudy of MEK162 Plus BYL719 in Adult Patients With Selected Advanced Solid TumorsAn immunotherapy or a vaccine trial or - e.g., NCT02403271 or NCT02468557 Study of Single AgentIdelalisib Followed by Idelalisib in Combination With Chemotherapy in Adults With MetastaticPancreatic Ductal AdenocarcinomaA non-biomarker-based pancreatic cancer trial - e.g., NCT01956812 Phase 3 Trial of 90Y-Clivatuzumab Tetraxetan & Gemcitabine vs Placebo & Gemcitabine in Metastatic Pancreatic Cancer

Other:

(3) Date of start of 1st therapy after the Perthera report?

(4) Performance status prior to start of new Therapy?

0 - Fully active

1 - Restricted physical activity; able to carry out work of a light or sedentary nature

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

3 - Capable of only limited self-care, confined to bed or chair more than 50% of the time

4 - Confined to bed or chair; cannot carry on any self-care

This analysis was sponsored by: Pancreatic Cancer Action Network®



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PATIENT DIAGNOSISPancreas ductal adenocarcinoma

DATE

SUMMARY

This patient has metastatic pancreatic cancer, and his disease progressed on FOLFOX. He was only able to tolerate a shortcourse of FOLFIRINOX due to toxicities. . He is currently on gemcitabine plus nab-paclitaxel. In preparation for the initiationof her next line of therapy, there are several options to consider:

There are options with FDA-approved (ON or OFF label) agents to consider•o MM-398 has been recently approved as second-line therapy, in combination with 5FU. He did not get treated

with irinotecan for a significant period of time, because of intolerance of FOLFIRINOX. Thus, with TOPO1expression positive in the tumor, it is possible that he might still benefit from MM-398 plus 5-FU (or FOLFIRI).

o A Phase II trial of capecitabine and ruxolitinib looked promising specifically in patients with high CRP levels.There is an ongoing trial for second-line therapy that this patient would not be eligible. However, one couldconsider “off-label” use of this combination if his CRP levels were elevated

There are clinical trials that would be worth consideration•o Based on the KRAS mutation, there may be downstream activation of MEK. Thus a clinical trial with a MEK

inhibitor may be an appropriate option. However, MEK inhibitors alone, or even in combination withchemotherapy have been ineffective in pancreatic cancer. So a combination of a MEK inhibitor plus anothersignal pathway inhibitor might be more promising. However, a previous SWOG trial targeting MEK and AKT inpancreas cancer did not show improved survival. There was also no benefit in colorectal cancer due to toxicitiesof treatment and inability to achieve target inhibition.

o Vaccine-based therapy or immunotherapy are both very promising, with a growing body of supportive data.Unfortunately, there have not been any reliable predictive markers of response identified to date.

PD-1 expression in the tumor infiltrating lymphocytes was positive – resulting in a possible increasedpotential for benefit from an anti-PD-1/anti-PDL1 antibody.

o There are several other pancreatic cancer trials that would be appropriate, that are not biomarker specific

As is recommended in the NCCN guidelines, most patients with pancreatic cancer should be considered for a clinical trial, ifthe trial is feasible for the patient

The scoring listed highlights how the treatment option aligns with the molecular profile, but is NOT meant to imply that anyone option has a greater chance of success.

Certain clinical trial options may have mentioned in the narrative, but are not listed as specific options below due to spacelimitations. All clinical trials are listed in the clinical trials section.



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CASE NUMBER DIAGNOSISPancreas ductal adenocarcinoma


Date of Birth

Gender

Case #

Client

Physician

MRN

Specimen Date

Specimen Site

__/__/____

Male

__________

__________

__________

2015-06-11

Lung

GENOMIC FINDINGS

Gene Result ImpliedBenefit

KDM6A V553fs*401KRAS amplificationKRAS Q61HROS1 NegativecMET Not Amplified -Her2/Neu Not Amplified -TOP2A Not Amplified -

PROTEIN FINDINGSProtein Result Implied

BenefitPD-1 Positive +PD-L1 Positive +TLE3 Positive +TOPO1 Positive +ERCC1 Positive -PTEN Positive -TUBB3 Positive -MLH1 PositiveMSH2 PositiveMSH6 PositivePMS2 PositiveTS Negative +ALK Negative -cMET Negative -Her2/Neu Negative - See Page 2 for Detailed Tumor Profile

FMI Case #: TRF119178Caris MI Profile #: TN15-115541

RANKED THERAPY OPTIONS (scoring details on page 6).

Therapy MolecularProfile

(max: 16)

DiseaseStats

(max: 8)

PatientHistory(max: 4)

Score(max: 28)

A Immunotherapy plus irinotecan-based chemotherapy - NCT02423954 5 7 2 14

B MM-398 plus 5FU or FOLFIRI 4 7 2 13

C Capecitabine + ruxolitinib 3 5 4 12

D A clinical trial of a MEK inhibitor combination or - e.g., NCT02022982 or NCT01449058 3 3 4 10

E An immunotherapy or a vaccine trial or - e.g., NCT02403271 or NCT02468557 3 3 4 10

F A non-biomarker-based pancreatic cancer trial - e.g., NCT01956812 0 3 4 7

These scores pertain to the molecular, disease-specific, and patient-specific relevance of the treatment options listed. Higher scores do not guarantee a greater chance of treatment success.Other considerations must be taken into account by the treating Physician. Additional appropriate clinical trials are listed on page 9.

SUMMARY INTERPRETATIONImmunotherapy plus irinotecan-based chemotherapy - NCT02423954: PD-L1 positive, TS expression negative, +1 TOPO1 positive; The chemotherapybackbone is a standard combination for pancreatic cancer; The patient has had prior 5FU and a brief period with irinotecan (

)MM-398 plus 5FU or FOLFIRI: TS expression negative, +1 TOPO1 positive; Standard combinations for pancreatic cancer; The patient has had prior 5FUand a brief period with irinotecan

Capecitabine + ruxolitinib: TS expression is negative; Promising data in a Phase II trial; The patient has not had these agents

A clinical trial of a MEK inhibitor combination or - e.g., NCT02022982 or NCT01449058: KRAS mutation; The patient has not had these agents ()

An immunotherapy or a vaccine trial or - e.g., NCT02403271 or NCT02468557: PD-L1 positive; The patient has not had this class of agents ()

A non-biomarker-based pancreatic cancer trial - e.g., NCT01956812: The patient has not had this class of agents ()

Only those patient factors provided to Perthera have been considered.Treating oncologist will consider complete patient history and current conditions.

+-

implied benefit indicates potential therapeutic benefit based on the biomarker indicated

implied benefit indicates potential LACK of therapeutic benefit based on the biomarker indicated

Tumor cell diagram unique to this patient based on profile from following assays:



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TUMOR PROFILEPatient UniqueMolecular ProfileTumor Diagram #1607

TUMOR CELL CYCLE and SIGNALING IMPLICATIONSThe programmed death 1 (PD-1) checkpoint pathway plays a key role in modulating the immune system. Sometumors exploit this pathway to evade the body's protective immune response to cancer.

PD-1 Positive

Aberrant expression of programmed cell death 1 ligands 1 and 2 (PD-Ls) on tumor cells dampens antitumor immunity,resulting in tumor immune evasion.

PD-L1 Positive

Transducin-Like Enhancer protein 3 (TLE3) supports DNA transcription. TLE3 also interacts with the Notch/Wntpathway. Positive TLE3 could contribute to tumor proliferation.

TLE3 Positive

Topoisomerase (TOPO1) supports DNA transcription and replication. Positive TOPO1 can increase the tumor’s abilityto replicate DNA and proliferate.

TOPO1 Positive

TUBB3 supports replication and contributes to cell survival through resistance to stress. Positive TUBB3 could maketumors drug resistant.

TUBB3 Positive

KRAS amplification is correlated with sensitivity of cancer cell lines to KRAS knockdown, suggesting that amplifiedKRAS is an oncogenic driver.

KRAS amplification

KRAS encodes a member of the RAS family of membrane proteins that bind GDP/GTP and possess GTPase activity.Mutations in RAS genes can cause uncontrolled cell proliferation and tumor formation.

KRAS Q61H

KDM6A encodes a histone H3 lysine 27 demethylase (also known as UTX) which is thought to be a tumor suppressorby virtue of its epigenetic regulation of transcription. KDM6A was inactivating and therefore is predicted to lead to lossof function.

KDM6A Inactivating Mutation



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DNA PROTEIN Implications / Comments

KRAS Q61HKRAS mutations may result in activation of downstream pathways, including theMAPK pathway.Therefore, inhibitors of MAPK pathway components, including the MEK proteins, may berelevantin a tumor with KRAS mutation.

KRAS amplificationKRAS activating mutations or amplification may result in activation of downstream pathways,including theMAPK pathway. Therefore, inhibitors of MAPK pathway components, including theMEK proteins, may berelevant in a tumor with KRAS mutation.

cMET Not Amplified C-met gene was Non-amplified suggesting lack of benefit with a c-met inhibitor. [1][2]

Her2/Neu Not Amplified Her2/neu was not amplified suggesting a lack of benefit from trastuzumab, pertuzumab, TDM-1, orlapatinib [3][4][5][6][7]

TOP2A Not Amplified TOP2A was not amplified suggesting a lack of benefit from anthracyclines [8][9][10][11][12][13]

PD-L1+,PD-1+PD-L1 expression in the tumor AND PD-1 expression in the tumor infiltrating lymphocytes werepositive – resulting in an increased potential for benefit from an anti-PD-1/anti-PDL1 antibody

TLE3 Positive TLE3 was positive, suggesting potential benefit with taxanes [14][15][16][17][18][19]

TOPO1 Positive TOPO1 was positive, suggesting potential benefit from irinotecan or topotecan [20][21][22]

ERCC1 PositiveERCC1 was positive, suggesting a LACK of benefit with platinums. However, the negativepredictive value of ERCC1 is not reliable. [23][24][25][26]

PTEN PositivePTEN expression was positive, suggesting a LACK of benefit with mTOR inhibitors or with PARPInhibitors [27][28][29]

TUBB3 Positive TUBB3 was positive, suggesting LACK of benefit with taxanes [14][15][30]

TS Negative TS expression was negative, suggesting potential benefit with 5-fluorouracil [31][32][33]

ALK Negative ALK was negative, suggesting a LACK of benefit with crizotinib or ceritinib [34][35],[36][37]

cMET Negative cMET expression was negative, suggesting a LACK of benefit from a c-met inhibitor [1][2]

Her2/Neu NegativeHER2 expression was negative by IHC, suggesting a LACK of benefit from trastuzumab,pertuzumab, TDM-1 or lapatinib [38][39][3][40][4][5][6][41][42][43]

THERAPY IMPLICATIONS



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PATIENT CONSIDERATIONS

• The patient is a 65 year old male who was diagnosed with metastatic pancreatic cancer with lung metastases on05/12/2015.

• He started first line therapy with FOLFIRINOX on 07/15/2015, which had to be reduced to just FOLFOX starting08/18/2015, for symptoms.

• His disease progressed and he started gemcitabine and nab-paclitaxel on 09/15/2015.

• This analysis is based on a lung biopsy on 06/15/2015.

Only those patient factors provided to Perthera have been considered.Treating oncologist will consider complete patient history and current conditions.

RELEVANT MEDICAL HISTORY

ADDITIONAL PERSPECTIVE



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TREATMENT NOTES

Important pertinent negative test results

ERCC1 was positive, suggesting a LACK of benefit with platinums [44][45][46]•TLE3 was positive, suggesting a possible benefit with taxanes; but TUBB3 was positive, suggesting a LACK of benefitwith taxanes. In summary, the predictive results indeterminate for benefit with the taxanes [47][48][16][49]

•

There was no evidence of mismatch repair enzyme deficiency by IHC, and the tumor was MSS by PCR.•Testing for RRM1 as a predictive marker for gemcitabine was not available•

There are FDA Approved drugs that could be of benefit

.•TOPO1 was positive, suggesting a possible benefit from irinotecan or topotecan [20][50][51]•

There are drugs in clinical trials that could be of benefitA KRAS Q61H mutation was identified. A KRAS mutation predicts for lack of response to anti-HER-family therapies suchas cetuximab/panitumumab and erlotinib or lapatinib, and presumably anti-HER-2 agents such as trastuzumab andpertuzumab. In theory, constitutively active KRAS mutations can be circumvented by targeting downstream on KRAS,such as with RAF/MEK/ERK inhibitors [52][53][54][55][56][57], though MEK inhibitors have not been beneficial inpancreatic cancer as single agents, or in combination with chemotherapy.

•

PD-L1 expression in the tumor, and PD-1 expression in the tumor-associated lymphocytes were positive suggesting apossible increased potential for benefit from an anti-PD-1/anti-PD-L1 antibody.

•



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THERAPY SCORING and RATIONALE (see Scoring Model on page 18)

Therapy Option Rationale Score

Immunotherapy plus irinotecan-basedchemotherapy - NCT02423954

Trial Description: Study of Nivolumab Plus Chemotherapy in Patients With AdvancedCancer (NivoPlus)Trial Closest Recruiting Site: (1661 miles) - Cancer Treatment Center of America @Western Regional Medical Center, Goodyear, AZTrial Contact: Research Nurse, 623-207-3000, [email protected]

Molecular relevance: PD-L1 positive, TS expression negative, +1 TOPO1 positive 5

Disease relevance: The chemotherapy backbone is a standard combination forpancreatic cancer

7

Patient relevance: The patient has had prior 5FU and a brief period with irinotecan 2

• FOLFIRI has proven benefit in pancreatic cancer[58][59]

• TS expression is negative, which predicts for a response to 5FU

• TOPO1 expression is positive, which predicts for a possible response to irinotecan

• Immunotherapy is a promising approach

14

MM-398 plus 5FU or FOLFIRI

Molecular relevance: TS expression negative, +1 TOPO1 positive 4

Disease relevance: Standard combinations for pancreatic cancer 7

Patient relevance: The patient has had prior 5FU and a brief period with irinotecan 2

• MM-398 plus 5-FU has proven benefit in pancreatic cancer[60]

• FOLFIRI has proven benefit in pancreatic cancer[58][59]

• TS expression is negative, which predicts for a response to 5FU

• TOPO1 expression is positive, which predicts for a possible response to irinotecan

13

Capecitabine + ruxolitinib

Molecular relevance: TS expression is negative 3

Disease relevance: Promising data in a Phase II trial 5

Patient relevance: The patient has not had these agents 4

• TS expression is negative, which predicts for a possible response to 5FU

• The Phase II study was promising for patients with high CRP levels 12

A clinical trial of a MEK inhibitorcombination or - e.g., NCT02022982 orNCT01449058

Trial Description: A Phase Ib Study of MEK162 Plus BYL719 in Adult Patients WithSelected Advanced Solid TumorsTrial Closest Recruiting Site: (202 miles) - Lurie Children's Hospital of Chicago OncDept., Chicago, ILTrial Contact: Amy Hoyer, 312-695-1341, [email protected]

Molecular relevance: KRAS mutation 3

Disease relevance: (Experimental) 3

Patient relevance: The patient has not had these agents 4

• Tumors with KRAS mutations in theory may respond to a MEK inhibitor

• MEK inhibitors alone or in combination with chemotherapy have NOT been of benefitin pancreatic cancer

• Combinations with other signaling inhibitors may be beneficial

• However, a recent SWOG trial did not show benefit for the combination of a MEKinhibitor and an AKT inhibitor

10



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Therapy Option Rationale Score

An immunotherapy or a vaccine trial or -e.g., NCT02403271 or NCT02468557

Trial Description: Study of Single Agent Idelalisib Followed by Idelalisib in CombinationWith Chemotherapy in Adults With Metastatic Pancreatic Ductal AdenocarcinomaTrial Closest Recruiting Site: (110 miles) - Indiana University Goshen Center for CancerCare, Goshen, INTrial Contact: Gilead Study Team, [email protected]

Molecular relevance: PD-L1 positive 3


Patient relevance: The patient has not had this class of agents 4

• Immunotherapy is a promising approach

• Unfortunately there are no specific biomarkers that predict for response

• Well tolerated10

A non-biomarker-based pancreaticcancer trial - e.g., NCT01956812

Trial Description: Phase 3 Trial of 90Y-Clivatuzumab Tetraxetan & Gemcitabine vsPlacebo & Gemcitabine in Metastatic Pancreatic CancerTrial Closest Recruiting Site: (56 miles) - Barbara Ann Karmanos Cancer Institute,Detroit, MITrial Contact: Colette Zack, 313-576-9385, [email protected]

Molecular relevance: (No predictive markers) 0


Patient relevance: The patient has not had this class of agents 4

• Unfortunately there are no specific biomarkers that predict for response to thesetherapies 7



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Note

This is randomized trial in which half of patients do NOT receive the experimental therapy. See https://clinicaltrials.gov/ct2/show/NCT01956812 So, Disease Relevance should be lower than 3.



Reviewer

REVIEWERS

This analysis has been reviewed by Perthera’s Medical Review Paneland a clinical oncologist who is an expert in this cancer type.



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Protocol Title Phase PotentialTarget Therapy Locations

Immunotherapy Trials

NCT02219724

A PHASE I, OPEN-LABEL, DOSE-ESCALATIONSTUDY OF THE SAFETY ANDPHARMACOKINETICS OF MOXR0916ADMINISTERED INTRAVENOUSLY AS A SINGLEAGENT TO PATIENTS WITH LOCALLY ADVANCEDOR METASTATIC SOLID TUMORS

Status: RecruitingClosest Recruiting Site: Chicago, ILDistance: 202milesContact: Reference Study ID Number: GO29313www.roche.com/about_roche/roche_worldwide.htm,888-662-6728 (U.S. Only),[email protected]

Phase 1 MOXR0916 AZ, CO, CT, DC, IL,MD, MA, NY, TN, WA

NCT02403271

A Multi-Center Study of the Bruton's Tyrosine Kinase(BTK) Inhibitor, Ibrutinib, in Combination WithMEDI4736, in Subjects With Relapsed or RefractorySolid Tumors

Status: RecruitingClosest Recruiting Site: Chicago, ILDistance: 202milesContact: Molly Mallough, 408-215-3743,[email protected]

Phase 1Phase 2 B7H1, BTK Ibrutinib,

MEDI4736AZ, CA, FL, IL, NJ,TN, TX

NCT01174121

A Phase II Study Using Short-Term Cultured,Autologous Tumor-Infiltrating Lymphocytes Followinga Lymphocyte Depleting Regimen in MetastaticCancers

Status: RecruitingClosest Recruiting Site: National Institutes of HealthClinical Center, 9000 Rockville Pike, Bethesda, MDDistance: 394milesContact: For more information at the NIH ClinicalCenter contact NCI/Surgery Branch RecruitmentCenter, 866-820-4505, [email protected]

Phase 2 (synthesis)

Young TIL,Aldesleukin,

Cyclophosphamide, Fludarabine

MD

NCT01583686

Phase I/II Study of Metastatic Cancer UsingLymphodepleting Conditioning Followed by Infusionof Anti-mesothelin Gene Engineered Lymphocytes

Status: RecruitingClosest Recruiting Site: National Institutes of HealthClinical Center, 9000 Rockville Pike, Bethesda, MDDistance: 394milesContact: For more information at the NIH ClinicalCenter contact NCI/Surgery Branch RecruitmentCenter, 866-820-4505, [email protected]

Phase 1Phase 2 (synthesis)

Fludarabine,Anti-mesothelin

CAR,Cycolphosphamide, Aldesleukin

MD

APPROPRIATE CLINICAL TRIALS

IMPORTANT: While every effort is made to ensure the accuracy of the information contained below, the informationavailable in the public domain is continuously updated and should be investigated by the physician or research staff. Thisis not meant to be a complete list of available trials.

As of 19 November 2015 we have identified the following appropriate clinical trials that are active and recruiting patients (unless otherwise noted).



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NCT01473940

Ipilimumab and Gemcitabine for Advanced PancreasCancer: A Phase Ib Study

Status: RecruitingClosest Recruiting Site: Northwestern University,Chicago, ILDistance: 202milesContact: Mary F. Mulcahy, 312-695-4440, [email protected]

Phase 1 CTLA4ipilimumab,gemcitabine

hydrochlorideIL

NCT02423954

A Phase Ib/II Study of Nivolumab Plus Chemotherapyin Patients With Advanced Cancer (NivoPlus)

Status: RecruitingClosest Recruiting Site: Cancer Treatment Center ofAmerica @ Western Regional Medical Center,Goodyear, AZDistance: 1661milesContact: Research Nurse, 623-207-3000,[email protected]

Phase 1Phase 2 PD-1, mTOR

Temsirolimus,Irinotecan,

Irinotecan +capecitabine,

nivolumab

AZ

NCT02468557

A Phase 1b Study of Single Agent Idelalisib Followedby Idelalisib in Combination With Chemotherapy inSubjects With Metastatic Pancreatic DuctalAdenocarcinoma

Status: RecruitingClosest Recruiting Site: Indiana University GoshenCenter for Cancer Care, Goshen, INDistance: 110milesContact: Gilead Study Team, [email protected]

Phase 1Idelalisib, Nab-

paclitaxel,mFOLFOX6

IN, AZ, DC, SC

NCT02318394

A Phase 1 Study to Evaluate the Safety, Tolerability,Pharmacokinetics, Pharmacodynamics, andPreliminary Clinical Activity of MEDI0562 in AdultSubjects With Selected Advanced Solid Tumors

Status: RecruitingClosest Recruiting Site: Research Site, Pittsburgh,PADistance: 214milesContact: AstraZeneca Clinical Study InformationCenter, 1-877-240-9479,[email protected]

Phase 1 MEDI0562 PA, CA, NY, NC, OR,TX

NCT01738139

A Phase I Trial of Ipilimumab (Immunotherapy) andImatinib Mesylate (c-Kit Inhibitor) in Patients WithAdvanced Malignancies

Status: RecruitingClosest Recruiting Site: University of Texas MDAnderson Cancer Center, Houston, TXDistance: 1055milesContact: David S. Hong, MD, 713-563-1930

Phase 1 CTLA4Ipilimumab,

ImatinibMesylate

TX

NCT02261220

A Phase I Study of MEDI4736 (Anti-PD-L1 Antibody)in Combination With Tremelimumab (Anti-CTLA-4Antibody) in Subjects With Advanced Solid Tumors

Status: RecruitingClosest Recruiting Site: Research Site, Cleveland,OHDistance: 105milesContact: AstraZeneca Clinical Study InformationCenter, 1-877-240-9479,[email protected]

Phase 1 B7H1 MEDI4736,tremelimumab

OH, AZ, CA, CO, FL,IL, NY, OR, SC, TX



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NCT01928394

A Phase 1/2, Open-label Study of NivolumabMonotherapy or Nivolumab Combined WithIpilimumab in Subjects With Advanced or MetastaticSolid Tumors

Status: RecruitingClosest Recruiting Site: Sidney KimmelComprehensive Cancer Center At Johns Hopkins,Baltimore, MDDistance: 409milesContact: Dung Le, Site 0004, 410-955-4429

Phase 1Phase 2 PD-1, CTLA4 Nivolumab,

IpilimumabCT, FL, GA, MD, MA,NY, NC, OR, TN, TX

NCT02303990

RADVAX: A Stratified Phase I Trial of PembrolizumabWith Hypofractionated Radiotherapy in Patients WithAdvanced and Metastatic Cancers

Status: RecruitingClosest Recruiting Site: Abramson Cancer Center ofthe University of Pennsylvania, Philadelphia, PADistance: 462milesContact: Amit Maity, MD, PhD,[email protected]

Phase 1 Pembrolizumab PA

NCT02309177

A Phase 1, Open-Label, Multicenter, Safety Study ofNivolumab (BMS-936558) in Combination With Nab-Paclitaxel Plus or Minus Gemcitabine in PancreaticCancer, Nab-Paclitaxel / Carboplatin in Stage IIIB/IVNon-Small Cell Lung Cancer or Nab-Paclitaxel inMetastatic Breast Cancer

Status: RecruitingClosest Recruiting Site: Ohio State Medical Center,Columbus, OHDistance: 123milesContact: Associate Director, Clinical Trial Disclosure,1-888-260-1599, [email protected]

Phase 1 PD-1

nab-Paclitaxel,Nivolumab,

Gemcitabine,Carboplatin

OH, PA, CA, CT, FL,MA, NJ, NC, WA, WI

NCT02362048

A Phase 2 Proof-of-Concept Study of ACP-196 Aloneand in Combination With Pembrolizumab in SubjectsWith Advanced or Metastatic Pancreatic Cancer

Status: RecruitingClosest Recruiting Site: Global Cancer ResearchInstitute, Gilroy, CADistance: 2028milesContact: Christine Hegi, 1-403-262-7176,[email protected]

Phase 2

ACP-196, ACP-196 in

combination withpembrolizumab

CA

MEK Inhibitor Trials

NCT02079740

An Open Label, Two-Part, Phase Ib/II Study toInvestigate the Safety, Pharmacokinetics,Pharmacodynamics, and Clinical Activity of the MEKInhibitor Trametinib and the BCL2-Family InhibitorNavitoclax (ABT-263) in Combination in SubjectsWith KRAS Mutation-Positive Advanced Solid Tumors

Status: RecruitingClosest Recruiting Site: Dana-Farber CancerInstitute, Boston, MADistance: 649milesContact: Geoffrey I. Shapiro, 617-632-4942,[email protected]

Phase 1Phase 2 Bcl-2, MEK1/2 Navitoclax,

Trametinib MA



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MEK Inhibitor Trials

NCT02022982

Phase I/II Study of the CDK4/6 Inhibitor Palbociclib(PD-0332991) in Combination With the MEK InhibitorPD-0325901 for Patients With KRAS Mutant Non-Small Cell Lung Cancer and Other Solid Tumors

Status: RecruitingClosest Recruiting Site: Dana Farber Cancer Institute,Boston, MADistance: 649milesContact: Andrew Wolanski, NP, 617-632-6623,[email protected]

Phase 1Phase 2 MEK, CDK4/6 Palbociclib, PD-

0325901 MA

NCT02065063

A Dose-Escalation, Phase I/II, Open-Label, Three-Part Study of the MEK Inhibitor, Trametinib,Combined With the CDK4/6 Inhibitor, Palbociclib, ToInvestigate the Safety, Pharmacokinetics,Pharmacodynamics, and Anti-Cancer Activity inSubjects With Solid Tumors

Status: RecruitingClosest Recruiting Site: GSK Investigational Site,Nashville, TNDistance: 415milesContact: US GSK Clinical Trials Call Center, 877-379-3718, [email protected]

Phase 1 CDK4/6, MEK1/2 Trametinib,Palbociclib MA, TN, TX

NCT01449058

A Phase Ib Open-label, Multi-center, Dose Escalationand Expansion Study of Orally Administered MEK162Plus BYL719 in Adult Patients With SelectedAdvanced Solid Tumors

Status: RecruitingClosest Recruiting Site: Lurie Children's Hospital ofChicago Onc Dept., Chicago, ILDistance: 202milesContact: Amy Hoyer, 312-695-1341,[email protected]

Phase 1Phase 2 MEK BYL719 plus

MEK162 CA, IL, MA, NY, UT

NCT01986166

A PHASE Ib, OPEN-LABEL, DOSE-ESCALATIONSTUDY OF THE SAFETY, TOLERABILITY, ANDPHARMACOKINETICS OF MEHD7945A and GDC-0973 IN PATIENTS WITH LOCALLY ADVANCED ORMETASTATIC SOLID TUMORS WITH MUTANTKRAS

Status: RecruitingClosest Recruiting Site: Nashville, TNDistance: 415milesContact: Reference Study ID Number: GO29030www.roche.com/about_roche/roche_worldwide.htm,888-662-6728 (U.S. Only),[email protected]

Phase 1 MEK1 MEHD7945A,cobimetinib CA, CO, CT, TN, TX



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Additional pancreatic cancer Trials

NCT01927965

A Phase 1, Multi-Center, Open-Label, Dose-Escalation, Safety, Pharmacokinetic, andPharmacodynamic Study of Minnelide™ Given Dailyfor 21 Days Followed by 7 Days Off Schedule inPatients With Advanced GI Tumors.

Status: RecruitingClosest Recruiting Site: University of MinnesotaMasonic Cancer Clinic, Minneapolis, MNDistance: 528milesContact: Carrie McCann, RN, 612-626-2569,[email protected]

Phase 1 Minnelide™ 001 AZ, MN

NCT01053013

An Open-Label Phase 2 Efficacy Trial of theImplantation of Mouse Renal Adenocarcinoma Cell-Containing Agarose-Agarose Macrobeads in theTreatment of Patients With Treatment-Resistant,Metastatic Pancreatic or Colorectal Adenocarcinoma

Status: RecruitingClosest Recruiting Site: The Rogosin Institute, NewYork, NYDistance: 510milesContact: Barry H Smith, MD, PhD, 212-746-1551,[email protected]

Phase 2

Cancermacrobead

placement inabdominal cavity

NY

NCT02009449

A Phase 1, Open-Label Dose Escalation First-in-Human Study to Evaluate the Tolerability, Safety,Maximum Tolerated Dose, and Pharmacokinetics ofAM0010 in Patients With Advanced Solid Tumors

Status: RecruitingClosest Recruiting Site: Sarah Cannon ResearchInstitute, Nashville, TNDistance: 415milesContact: Ainslie Rogers, 615-524-4155,[email protected]

Phase 1 VEGFR / PDGF-R / c-kit

AM0010,Paclitaxel or

Docetaxel andCarboplatin or

Cisplatin,FOLFOX

(Oxaliplatin/Leucovorin/5-

Fluorouracil),gemcitabine/nab-

paclitaxel,Capecitabine,

Pazopanib,Pembrolizumab,

Paclitaxel

CA, CO, FL, MA, NY,OK, TN, TX

NCT01956812

An International, Multi-Center, Double-Blind,Randomized, Phase III Trial of 90Y-ClivatuzumabTetraxetan Plus Low-Dose Gemcitabine VersusPlacebo Plus Low-Dose Gemcitabine in Patients WithMetastatic (Stage IV) Pancreatic AdenocarcinomaWho Received at Least Two Prior Treatments(PANCRIT-1)

Status: RecruitingClosest Recruiting Site: Barbara Ann KarmanosCancer Institute, Detroit, MIDistance: 56milesContact: Colette Zack, 313-576-9385,[email protected]

Phase 3IMMU-107,

placebo,Gemcitabine

OH, MI, IN, PA, AZ,CA, CT, FL, ID, IL,MD, MN, MS, NE, NV,NH, NY, NC, OK, TN,TX, VA, WA

NCT01783171

A Phase I Trial of Dinaciclib (SCH727965) and MK-2206 in Metastatic Pancreatic Cancer With anExpansion Cohort in Advanced Pancreatic Cancer

Status: RecruitingClosest Recruiting Site: University of WisconsinHospital and Clinics, Madison, WIDistance: 306milesContact: Noelle K. LoConte, 608-265-5883,[email protected]

Phase 1 CDKAkt Inhibitor

MK2206,Dinaciclib

CO, MD, WI



Phone: 877-827-7893Fax: 888-965-8043

13




Additional pancreatic cancer Trials

NCT01804530

A Phase 1 Study to Assess Safety,Pharmacokinetics, and Pharmacodynamics ofPLX7486 as a Single Agent and in Combination WithGemcitabine and Nab-Paclitaxel in Patients WithAdvanced Solid Tumors

Status: RecruitingClosest Recruiting Site: Plexxikon Investigative Site,Charleston, SCDistance: 649milesContact: David Karlin, MD, 510-647-4100,[email protected]

Phase 1PLX7486 TsOH,

Gemcitabine,nab-Paclitaxel

CA, SC

NCT02202785

A Phase 2 Trial of MLN0264 in Previously TreatedPatients With Advanced or Metastatic PancreaticAdenocarcinoma Expressing Guanylyl Cyclase C(GCC)

Status: RecruitingClosest Recruiting Site: Nashville, TNDistance: 415milesContact: Millennium Medical and Drug InformationCenter, 1-877-674-3784, [email protected]

Phase 2 MLN0264 OH, CO, FL, MA, TN,TX

NCT02101580

Phase 1B Trial of ADI-PEG 20 Plus Nab-Paclitaxeland Gemcitabine in Subjects With AdvancedPancreatic Cancer

Status: RecruitingClosest Recruiting Site: Memorial Sloan-KetteringCancer Center, New York, NYDistance: 510milesContact: Adalberto Barba, MD, 858-452-6688,[email protected]

Phase 1 ADI-PEG 20 NY

NCT02080260

A Pilot Study Testing Single-Agent Regorafenib inAdvanced Previously-Treated Adenocarcinoma of thePancreas

Status: RecruitingClosest Recruiting Site: Levine Cancer Institute -Cleveland, Shelby, NCDistance: 456milesContact: Neil L West, RN, 704-863-6187,[email protected]

Phase 2VEGFR / Ret /Kit / PDGFR /

Rafregorafenib NC, SC



Phone: 877-827-7893Fax: 888-965-8043

14



Drug Data

fluorouracil(Adrucil, Efudex, Fluoroplex)[Ro-2-9757]

An antimetabolite fluoropyrimidine analog of the nucleoside pyrimidine with antineoplastic activity. Fluorouracil and itsmetabolites possess a number of different mechanisms of action. In vivo, fluoruracil is converted to the active metabolite 5-fluoroxyuridine monophosphate (F-UMP); replacing uracil, F-UMP incorporates into RNA and inhibits RNA processing,thereby inhibiting cell growth. Another active metabolite, 5-5-fluoro-2'-deoxyuridine-5'-O-monophosphate (F-dUMP), inhibitsthymidylate synthase, resulting in the depletion of thymidine triphosphate (TTP), one of the four nucleotide triphosphatesused in the in vivo synthesis of DNA. Other fluorouracil metabolites incorporate into both RNA and DNA; incorporation intoRNA results in major effects on both RNA processing and functions.

irinotecan(Camptosar, Campto)[CPT-11, U-101440E]

The hydrochloride salt of a semisynthetic derivative of camptothecin, a cytotoxic, quinoline-based alkaloid extracted from theAsian tree Camptotheca acuminata. Irinotecan, a prodrug, is converted to a biologically active metabolite 7-ethyl-10-hydroxy-camptothecin (SN-38) by a carboxylesterase-converting enzyme. One thousand-fold more potent than its parent compoundirinotecan, SN-38 inhibits topoisomerase I activity by stabilizing the cleavable complex between topoisomerase I and DNA,resulting in DNA breaks that inhibit DNA replication and trigger apoptotic cell death. Because ongoing DNA synthesis isnecessary for irinotecan to exert its cytotoxic effects, it is classified as an S-phase-specific agent.

irinotecan liposome(Onivyde)[PEP02]

A liposomal formulation of the hydrochloride salt of the semisynthetic camptothecin analogue irinotecan with potentialantineoplastic activity. During the S phase of the cell cycle, irinotecan selectively stabilizes topoisomerase I-DNA covalentcomplexes, inhibiting religation of topoisomerase I-mediated single-strand DNA breaks and producing lethal double-strandDNA breaks when complexes are encountered by the DNA replication machinery. Liposome encapsulation of this agentpromotes efficient drug delivery into the cytosol from the endosome compartment of the cell.

DATA ON DRUGS IN RANKED THERAPIES



Phone: 877-827-7893Fax: 888-965-8043

15



Drug Data

pegylated arginine deiminase

An agent consisting of the arginine-degrading enzyme arginine deiminase combined with polyethylene glycol (20,000 MW)(ADI-PEG 20) with potential antineoplastic activity. Upon administration, arginine deiminase breaks down the amino acidarginine into citrulline. Although arginine is a nonessential amino acid for normal human cells, certain cancer cells areautotrophic for arginine and need arginine in order to survive. Depletion of arginine may lead to an inhibition of cellularproliferation in those cancer cells. ADI is coupled to PEG in order to enhance this agent's half-life.

Akt inhibitor MK2206[MK2206]

An orally bioavailable allosteric inhibitor of the serine/threonine protein kinase Akt (protein kinase B) with potentialantineoplastic activity. Akt inhibitor MK2206 binds to and inhibits the activity of Akt in a non-ATP competitive manner, whichmay result in the inhibition of the PI3K/Akt signaling pathway and tumor cell proliferation and the induction of tumor cellapoptosis. Activation of the PI3K/Akt signaling pathway is frequently associated with tumorigenesis and dysregulatedPI3K/Akt signaling may contribute to tumor resistance to a variety of antineoplastic agents.

pegylated recombinant humaninterleukin-10 AM0010[AM0010]

A covalent conjugate of recombinant human interleukin-10 (IL-10) and polyethylene glycol (PEG), with potential anti-fibrotic,anti-inflammatory, immunomodulating and antineoplastic activities. Upon subcutaneous administration, pegylatedrecombinant human interleukin-10 AM0010 may activate cell-mediated immunity against cancer cells by stimulating thedifferentiation and expansion of tumor specific cytotoxic CD8+ T cells. This agent may also lower serum cholesterol levelsand reduce atherosclerotic plaques by inhibiting the synthesis of pro-inflammatory cytokines, such as Interferon-gamma, IL-2,IL-3, TNF-alpha, and GM-CSF. The PEG moiety inhibits proteolytic breakdown and clearance of AM0010, which prolongs itshalf-life, extends the duration of its therapeutic effects and allows less frequent dosing.

capecitabine(Xeloda)[Ro 09-1978/000]

A fluoropyrimidine carbamate belonging to the class of antineoplastic agents called antimetabolites. As a prodrug,capecitabine is selectively activated by tumor cells to its cytotoxic moiety, 5-fluorouracil (5-FU); subsequently, 5-FU ismetabolized to two active metabolites, 5-fluoro-2-deoxyuridine monophosphate (FdUMP) and 5-fluorouridine triphosphate(FUTP) by both tumor cells and normal cells. FdUMP inhibits DNA synthesis and cell division by reducing normal thymidineproduction, while FUTP inhibits RNA and protein synthesis by competing with uridine triphosphate for incorporation into theRNA strand.

carboplatin(Paraplat, Paraplatin,Blastocarb)[JM-8]

A second-generation platinum compound with a broad spectrum of antineoplastic properties. Carboplatin contains a platinumatom complexed with two ammonia groups and a cyclobutane-dicarboxyl residue. This agent is activated intracellularly toform reactive platinum complexes that bind to nucleophilic groups such as GC-rich sites in DNA, thereby inducing intrastrandand interstrand DNA cross-links, as well as DNA-protein cross-links. These carboplatin-induced DNA and protein effectsresult in apoptosis and cell growth inhibition. This agent possesses tumoricidal activity similar to that of its parent compound,cisplatin, but is more stable and less toxic.

cisplatin(Platinol, Platinol-AQ,Abiplatin)

An inorganic platinum agent (cis-diamminedichloroplatinum) with antineoplastic activity. Cisplatin forms highly reactive,charged, platinum complexes which bind to nucleophilic groups such as GC-rich sites in DNA, inducing intrastrand andinterstrand DNA cross-links, as well as DNA-protein cross-links. These cross-links result in apoptosis and cell growthinhibition.

docetaxel(Taxotere, Taxotere injectionconcentrate, Docecad)[RP 56976]

A semi-synthetic, second-generation taxane derived from a compound found in the European yew tree Taxus baccata.Docetaxel displays potent and broad antineoplastic properties; it binds to and stabilizes tubulin, thereby inhibiting microtubuledisassembly which results in cell- cycle arrest at the G2/M phase and cell death. This agent also inhibits pro-angiogenicfactors such as vascular endothelial growth factor (VEGF) and displays immunomodulatory and pro-inflammatory propertiesby inducing various mediators of the inflammatory response. Docetaxel has been studied for use as a radiation-sensitizingagent.

FOLFOX[FOLinic acid-Fluororuracil-OXaliplatin regimen]

One of several chemotherapy regimens that include leucovorin calcium (calcium folinate), 5-fluorouracil and oxaliplatin andwhich may be used in the treatment of advanced-stage and metastatic colorectal cancer. FOLFOX regimens differ in agentdosing and administration schedule and include FOLFOX 4, FOLFOX 6, modified FOLFOX 6 (mFOLFOX 6) and FOLFOX 7.

gemcitabine(Gemzar)[LY-188011]

The hydrochloride salt of an analogue of the antimetabolite nucleoside deoxycytidine with antineoplastic activity. Gemcitabineis converted intracellularly to the active metabolites difluorodeoxycytidine di- and triphosphate (dFdCDP, dFdCTP). dFdCDPinhibits ribonucleotide reductase, thereby decreasing the deoxynucleotide pool available for DNA synthesis; dFdCTP isincorporated into DNA, resulting in DNA strand termination and apoptosis.

yttrium Y 90 clivatuzumabtetraxetan[90Y-ClivatuzumabTetraxetan, 90Y-Clivatuzumab, 90Y-hPAM4,IMMU-107]

A radioimmunoconjugate comprised of the humanized monoclonal antibody HuPAM4, directed against the pancreatic cancerantigen MUC1, that is conjugated to the chelating agent tetra-azacyclododecanetetra-acetic acid (DOTA) and radiolabeledwith the beta-emitting radioisotope Yttrium Y90. Yttrium Y 90 clivatuzumab tetraxetan binds to tumor cells expressing MUC1antigen, selectively delivering a cytotoxic dose of beta radiation.

leucovorin calcium(Wellcovorin, Adinepar,Calcifolin)

An active metabolite of folic acid (also called folinic acid and citrovorum factor), which does not require metabolism bydihydrofolate reductase, the molecular target of folate antagonist-type chemotherapeutic drugs. Leucovorin calciumcounteracts the toxic effects of these medications, 'rescuing' the patient while permitting the antitumor activity of the folateantagonist. This agent also potentiates the effects of fluorouracil and its derivatives by stabilizing the binding of the drug'smetabolite to its target enzyme, thus prolonging drug activity.

DATA ON OTHER DRUGS IN RELEVANT TRIALS



Phone: 877-827-7893Fax: 888-965-8043

16



Drug Data

triptolide analogue(Minnelide)

A water soluble analogue of the diterpenoid triepoxide triptolide isolated from the Chinese herb Tripterygium wilfordii Hook Fwith potential antineoplastic activity. Upon intravenous administration, the triptolide analogue inhibits heat shock protein 70(HSP70) and prevents HSP70-mediated inhibition of apoptosis. This leads to both the induction of apoptosis and a reductionof cancer cell growth. HSP70, a molecular chaperone upregulated in various cancer cells, plays a key role in the inhibition ofcaspase-dependent and -independent apoptosis.

anti-GCC antibody-drugconjugate MLN0264[MLN0264]

An antibody-drug conjugate (ADC) containing a monoclonal antibody directed against guanylyl cyclase C (GCC or GUCY2C)conjugated to monomethylauristatin E (MMAE), an auristatin derivative and a potent microtubule inhibitor, with potentialantineoplastic activity. The monoclonal antibody moiety of MLN0264 selectively binds to GCC, a transmembrane receptornormally found on intestinal cells and dopamine neurons in the brain, but is also overexpressed on the surface ofgastrointestinal cancers. Upon internalization and proteolytic cleavage, MMAE binds to tubulin and inhibits its polymerization,resulting in G2/M phase arrest and tumor cell apoptosis in GCC-expressing tumor cells.

paclitaxel albumin-stabilizednanoparticle formulation(Abraxane)[ABI-007]

A Cremophor EL-free, albumin-stabilized nanoparticle formulation of the natural taxane paclitaxel with antineoplastic activity.Paclitaxel binds to and stabilizes microtubules, preventing their depolymerization and so inhibiting cellular motility, mitosis,and replication. This formulation solubilizes paclitaxel without the use of the solvent Cremophor, thereby permitting theadministration of larger doses of paclitaxel while avoiding the toxic effects associated with Cremophor.

oxaliplatin(Eloxatin, Dacotin, Dacplat)[JM-83, RP-54780, SR-96669]

An organoplatinum complex in which the platinum atom is complexed with 1,2-diaminocyclohexane (DACH) and with anoxalate ligand as a 'leaving group.' A 'leaving group' is an atom or a group of atoms that is displaced as a stable speciestaking with it the bonding electrons. After displacement of the labile oxalate ligand leaving group, active oxaliplatin derivatives,such as monoaquo and diaquo DACH platinum, alkylate macromolecules, forming both inter- and intra-strand platinum-DNAcrosslinks, which result in inhibition of DNA replication and transcription and cell-cycle nonspecific cytotoxicity. The DACHside chain appears to inhibit alkylating-agent resistance.

paclitaxel(Taxol, Anzatax, Asotax)

A compound extracted from the Pacific yew tree Taxus brevifolia with antineoplastic activity. Paclitaxel binds to tubulin andinhibits the disassembly of microtubules, thereby resulting in the inhibition of cell division. This agent also induces apoptosisby binding to and blocking the function of the apoptosis inhibitor protein Bcl-2 (B-cell Leukemia 2).

pazopanib(Votrient)[GW786034B]

The hydrochloride salt of a small molecule inhibitor of multiple protein tyrosine kinases with potential antineoplastic activity.Pazopanib selectively inhibits vascular endothelial growth factor receptors (VEGFR)-1, -2 and -3, c-kit and platelet derivedgrowth factor receptor (PDGF-R), which may result in inhibition of angiogenesis in tumors in which these receptors areupregulated.

pembrolizumab(Keytruda)[MK-3475, SCH 900475]

A humanized monoclonal immunoglobulin (Ig) G4 antibody directed against human cell surface receptor PD-1 (programmeddeath-1 or programmed cell death-1) with potential immune checkpoint inhibitory and antineoplastic activities. Uponadministration, pembrolizumab binds to PD-1, an inhibitory signaling receptor expressed on the surface of activated T cells,and blocks the binding to and activation of PD-1 by its ligands, which results in the activation of T-cell-mediated immuneresponses against tumor cells. The ligands for PD-1 include programmed cell death ligand 1 (PD-L1), overexpressed oncertain cancer cells, and programmed cell death ligand 2 (PD-L2), which is primarily expressed on APCs. Activated PD-1negatively regulates T-cell activation and plays a key role in in tumor evasion from host immunity.

Fms/Trk tyrosine kinaseinhibitor PLX7486[plx7486-tsoh, PLX7486]

The tosylate salt form of PLX7486, a selective inhibitor of the receptor tyrosine kinases colony-stimulating factor-1 receptor(CSF1R; fms) and neurotrophic tyrosine kinase receptor types 1, 2 and 3 (TrkA, TrkB, and TrkC, respectively) with potentialantineoplastic activity. Upon administration, PLX7486 binds to and inhibits the activity of these tyrosine kinases. This inhibitsFms and Trk-mediated signaling transduction pathways that are upregulated in certain cancer cell types. This may eventuallyhalt tumor cell proliferation in Fms and TrkA, TrkB, and/or TrkC-overexpressing tumor cells. Fms and TrkA, TrkB, and TrkCare receptor tyrosine kinases that are upregulated or mutated in a variety of tumors and promote tumor cell proliferation andsurvival.

regorafenib(Stivarga)[BAY 73-4506]

An orally bioavailable small molecule with potential antiangiogenic and antineoplastic activities. Regorafenib binds to andinhibits vascular endothelial growth factor receptors (VEGFRs) 2 and 3, and Ret, Kit, PDGFR and Raf kinases, which mayresult in the inhibition of tumor angiogenesis and tumor cell proliferation. VEGFRs are receptor tyrosine kinases that playimportant roles in tumor angiogenesis; the receptor tyrosine kinases RET, KIT, and PDGFR, and the serine/threonine-specificRaf kinase are involved in tumor cell signaling.



Phone: 877-827-7893Fax: 888-965-8043

17



PERTHERA THERAPY SCORING MODEL

rev 3-14a



Phone: 877-827-7893Fax: 888-965-8043

18



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