September, 2006 GIST Clinical Trials Life Fest 2006 Jerry Call

Novartis video   GIST-Gleevec video GIST-Gleevec video

Why do Patients Participate in Trials*?  89%-Obtaining possible benefit “very important”  17%-Helping future cancer patients/treatments  Other factors cited as “very important” 66%-Trust in doctor 66%-Trust in doctor 66%-Being treated by the latest treatment available 66%-Being treated by the latest treatment available 61%-Better standard of care and closer follow-up 61%-Better standard of care and closer follow-up  71% stated that “surviving for as long as possible” was the most important thing for them *Survey of 38 patients participating in phase I and phase II trials British Journal of Cancer (2005) 92, British Journal of Cancer (2005) 92,

Trial phases  Phase I First step in humans First step in humans Increasing doses (cohorts) determine safe dose Increasing doses (cohorts) determine safe dose Evaluate route of administration Evaluate route of administration Side effects Side effects  Phase II Further defines the safety and begins to evaluate effectiveness Further defines the safety and begins to evaluate effectiveness  Phase III Compare a new agent with the current standard treatment. Compare a new agent with the current standard treatment. Randomized to groups Randomized to groups  Phase IV Usually take place after the treatment is approved Usually take place after the treatment is approved Further evaluate long-term safety and effectiveness Further evaluate long-term safety and effectiveness

High Patient Interest in GIST Trials  Success of Glivec  But also, an educated patient population Internet-based support groups Internet-based support groups  Patients continue to join trials of new therapies for GIST SU11248, AMG706, RAD001, PKC412, BMS , AMN107, BAY SU11248, AMG706, RAD001, PKC412, BMS , AMN107, BAY Early success- high expectations. GIST patients spoiled by the initial success. Early success- high expectations. GIST patients spoiled by the initial success.

Patients use clinical trials to survive  Access to the latest drugs  Medical team that is more familiar with GIST  Medical treatment and monitoring are usually better  Clinical trials move GIST research forward  May be a last resort/last chance

Factors Affecting Choice in Trials  Location  Travel How far? How far? How often? How often? How long do you have to say? How long do you have to say?  Phase  Eligibility Inclusion/exclusion Insurance coverage National health care issues  Placebo vs. non- placebo  Early perception Efficacy, side effects, etc

Finding Clinical Trials    

Navigating Clinical Trials  Phase l: Starting at the right dosage level  Determining Eligibility  Logistic and Financial Issues Where is the trial site? Where is the trial site? Am I eligible to go there? Am I eligible to go there? How often to I have to go there? How often to I have to go there? For how long? For how long? At what costs? At what costs?

Previous Treatment Exclusions  Participation in some trials may prevent entry into other trials  Example: Phase II AMG706 does not allow previous inhibitors of c-Kit (except Glivec) or VEGF inhibitors (SU11248, PTK787, Avastin).  How do we maximize the chance for success for both patients and trials?

Failure to Inhibit KIT-secondary mutations Possible Solutions: Different KIT inhibitor with activity against both the primary and secondary mutation. Possibilities include: Sutent (approved in US) AMG706 (closed) BMS BAY Destroy KIT protein IPI-504 Combinations; Gleevec + AMN107, PKC412, etc In addition to the initial mutation, secondary mutations that promote resistance to Gleevec can occur. Prior to treatment with Gleevec none of 112 GIST samples had more than one activating mutation in KIT or PDGFRA (Heinrich MC, et al. J Clin Oncol : ) Initial and secondary KIT mutations Ligand binding domain Exon 9-Extracellular domain Exon 11-Juxtamembrane domain Exon 13-Tyrosine kinase domain 1 Exon 17-Tyrosine kinase domain 2 Kinase insert Cell membrane Common initial mutations

TrialDescription Phase II Study of Adjuvant Imatinib Mesylate in Patients With Completely Resected High-Risk Primary GIST (ACOSOG-Z9000) End points: survival, 2- and 5-year recurrence rates, toxicity; imatinib therapy initiated within 84 days of surgical resection, continuing for 1 year; enrollment complete (N = 110) Phase III Randomized Study of Adjuvant Imatinib Mesylate in Patients With Resected Primary GIST (ACOSOG-Z9001) End points: overall, recurrence-free survival; imatinib or placebo administered postoperatively for 1 year, with crossover to imatinib if recurrence; projected enrollment = 380 EORTC Soft Tissue and Bone Sarcoma Group End points: overall, recurrence-free survival; risk stratification/randomization after complete GIST resection to imatinib or no treatment for 2 years; projected enrollment = 400 Scandinavian Sarcoma Group Trial SSGXVIII End points: recurrence-free survival, safety, overall survival; imatinib administered postoperatively for 12 or 36 months; projected enrollment = 80 Phase II Study of Neoadjuvant and Adjuvant Imatinib Mesylate in Patients With Primary or Recurrent Potentially Resectable Malignant GIST (RTOG- S0132 End points: progression-free survival, objective response rate, safety; 8 weeks of imatinib therapy, then surgical debulking of all gross tumor and reinstitution of imatinib for 2 years; projected enrollment = 63 GIST indicates gastrointestinal stromal tumor; ACOSOG, American College of Surgeons Oncology Group; EORTC, European Organization for Research and Treatment of Cancer; RTOG, Radiation Therapy Oncology Group. Surgery and Imatinib for GIST: Clinical Trials

AKT/mTOR MAPK KIT PI3K Jak/Stat 3 Survive-grow SurviveProliferate PLC gamma PI3K - a central player – But no drug yet! KIT and downstream pathways are often targets in clinical trials PKC-θ

Inhibition target GIST882 Exon 13 (k642E) GIST430 Exon 11 (V560D)+ Exon 13 (V654A) GIST48 Exon 11+ Exon 17 (D820A) PI3-K MEK/MAPK mTOR PLC-gamma Cell lines with secondary KIT mutations were hyperactivated. KIT activation levels were 3 to 6 times higher than the cell line with a single KIT mutation. *Bauer et al, 2005 ASCO Effects of signaling inhibition on proliferation in GIST cell lines*

KIT Gleevec-SU11248-BMS AMG706-AMN107 PKC412-BAY HSP-90 inhibitors (indirect) PI3K AKT Perifosine mTOR RAD001-CCI779 AP Rapamycin DAG PKC-θ RAS R SCH66336 RAF-1 BAY MEK MAPK JAK2 STAT3 PTEN BCL-2 Gentasense PLC STAT1 BCL-X L BAD Ca2 CAI Src/Fyn/Lyn BMS Survive-grow Survive Proliferate VEGF Avastin-Su11248-BAY PKC412-AMG706 New blood vessel growth

Drugs in GIST trials  Sutent  BAY  BMS  IPI-504  CCI-779 (complete)  AMG706 (complete)  AMN107 + Gleevec  RAD001 + Gleevec  PKC412 + Gleevec  Perifosine + Gleevec  Genasense + Gleevec Future Trials? Avastin + Gleevec OSI-930

Sarcoma Trials that allow GIST  Doxorubicin + Flavopiridol Phase I-MSKCC Phase I-MSKCC Flavopiridol is an inhibitor of the cell cycle and an inhibitor of transcription Flavopiridol is an inhibitor of the cell cycle and an inhibitor of transcription  FR Phase II Phase II Belongs to a new class of chemotherapy drugs called histone deacetylase inhibitors (HDAC inhibitors). This is a class of drugs that works at a higher level within the cell-acting on the genome, which is like the master control room for all of the genes in a cell. Belongs to a new class of chemotherapy drugs called histone deacetylase inhibitors (HDAC inhibitors). This is a class of drugs that works at a higher level within the cell-acting on the genome, which is like the master control room for all of the genes in a cell.

Drug Targets GleevecKITPDGFRαPDGFRßBcr/abl SutentKITPDGFRαPDGFRßVEGFRFLT3 AMG706KITPDGFRαPDGFRßVEGFRRET BAY439006KITPDGFRßVEGFRFLT3RET AMN107KITPDGFRαPDGFRßBcr/abl BMS354825KITPDGFRα?Bcr/ablSCR PKC412KITPDGFRαPDGFRßVEGFRPKCFLT3 RAD001mTOR CCI-779mTOR AP23573mTOR RapamycinmTOR PerifosineAKT? GenasenseBcl-2 IPI-504HSP90KITAKTVEGF? 17DMAGHSP90KITAKTVEGF? OSI930KITVEGFR?

Sutent  Pfizer Oncology  Other names SU11248 (sometimes appears as SU011248) SU11248 (sometimes appears as SU011248) Sugen Sugen Sunitinib malate (the generic name) Sunitinib malate (the generic name)  TKI-KIT, PDGFR, FLT-3, VEGF  Only drug with proven ability against Gleevec resistant GIST  Approved in the United States, Canada and the U.K. Europe? Europe?  Available in other countries via a “Treatment use protocol” administered by EmergingMed ( )  Phase II continuous use trial is closed  New phase IIIb trial will test 800 mg Gleevec vs. continuous use Sutent (37.5 mg) in GIST that is resistant to 400 mg Gleevec.

Sutent-2  Gleevec-resistant GIST highly sensitive to SU11248 KIT KIT Exon 9Exon 9 Wild-type for KIT & PDGFRAWild-type for KIT & PDGFRA Secondary exon 13 or 14Secondary exon 13 or 14  Gleevec-resistant GIST less sensitive to SU11248 KIT exon 11 KIT exon 11 KIT secondary exon 17, exon 18 mutations KIT secondary exon 17, exon 18 mutations

Sutent concerns  Increased activity/growth during the “off cycle”?  Side effects Heart toxicity? Is this concern overrated? Heart toxicity? Is this concern overrated? Hypertension Hypertension Increased fatigue Increased fatigue

AMN107 (+ Gleevec)  Phase I/II GIST trials underway US US BostonBoston PhiladelphiaPhiladelphia Europe Europe Leuven, BelgiumLeuven, Belgium Lyon, FranceLyon, France Berlin, GermanyBerlin, Germany Milan, ItalyMilan, Italy  AMN107 targets Bcr/Abl, KIT and PDGFRA (the same targets as Gleevec)  The combination of AMN107 and Gleevec may provide a broad spectrum of activity against different primary and secondary mutations  Compassionate use  Registration trial-Fall of 2006?

mTOR as a target  mTOR is a downstream protein in the KIT and PDGFR pathways  Three mechanisms of anti-tumor activity: Tumor cell shrinkage Tumor cell shrinkage Cell cycle arrest at late G1 Cell cycle arrest at late G1 Anti-angiogenesis Anti-angiogenesis

mTOR inhibitors  RAD001 In phase I trials in combination with Gleevec. RAD001 is approved for transplant patients in many European countries In phase I trials in combination with Gleevec. RAD001 is approved for transplant patients in many European countries  AP23573 Ongoing sarcoma trials. GIST? Ongoing sarcoma trials. GIST?  CCI-779 Ongoing phase II GIST trial as a single agent Ongoing phase II GIST trial as a single agent  Rapamycin (Rapamune) Earliest mTOR inhibitor (least advanced?) Earliest mTOR inhibitor (least advanced?) Approved for transplant patients in many countries Approved for transplant patients in many countries

BMS  TKI inhibitor of Bcr-Abl, KIT, PDGFRA, Src  Activity against both the inactive and active kinase conformations of Bcr-Abl (and also KIT?)  Effective against 14 of 15 Gleevec resistant CML mutations  Not effected by p-glycoprotein MDR efflux pump  300 to 650 times more potent than Gleevec against Gleevec resistant CML lines  Less effective for KIT? For GIST, may need to be dosed near the MTD

Perifosine and Genasense  Perifosine Small molecule inhibitor of AKT. Small molecule inhibitor of AKT. AKT is an anti-apoptosis protein. Inhibition of AKT may enhance therapy. AKT is an anti-apoptosis protein. Inhibition of AKT may enhance therapy. Phase II trial combining Gleevec + Perifosine at MDACC. Phase II trial combining Gleevec + Perifosine at MDACC.  Genasense An antisense drug that inhibits bcl-2, an anti-apoptosis protein. Inhibition of bcl-2 may enhance therapy. An antisense drug that inhibits bcl-2, an anti-apoptosis protein. Inhibition of bcl-2 may enhance therapy. Phase II trial at MDACC is accruing patients. The trial combines Gleevec + Genasense. Four more trial sites are pending activation. Phase II trial at MDACC is accruing patients. The trial combines Gleevec + Genasense. Four more trial sites are pending activation.

BAY  Known as a RAF kinase inhibitor, but also a powerful KIT inhibitor, as well as VEGFR2  RAF is part of the MAPK downstream pathway in KIT and PDGFR Inhibition of multiple kinases may be more effective (KIT, RAF, VEGF) Inhibition of multiple kinases may be more effective (KIT, RAF, VEGF) Inhibits PDGFRß, but not PDGFRα Inhibits PDGFRß, but not PDGFRα  Several responses in Imatinib-resistant GIST have been reported  FDA approved for advanced kidney cancer  Phase II GIST trials at Univ. of Chicago and other centers

IPI-504  HSP90 inhibitors 17AAG (poor drug-like qualities) 17AAG (poor drug-like qualities) Would participation in a trial of 17AAG preclude entry into a trial with one of the newer drugs?Would participation in a trial of 17AAG preclude entry into a trial with one of the newer drugs? 17DMAG 17DMAG IPI-504 Infinity Pharmaceuticals phase I trial is open at Dana-Farber (no results yet) IPI-504 Infinity Pharmaceuticals phase I trial is open at Dana-Farber (no results yet)  Next generation may include oral drugs CNF20204 (Conforma) CNF20204 (Conforma)  The stronger KIT activation, the better the drug works

HSP90  The HSP90 protein helps to fold proteins into their proper conformation and protects client proteins  Improperly folded proteins are not functional and are destroyed within the cell  HSP90 inhibitors degrade KIT and other proteins in GIST Will the lack of specificity contribute to side effects? Will the lack of specificity contribute to side effects?OR Will the broad-activity contribute to anti-tumor effects? Will the broad-activity contribute to anti-tumor effects?  In theory works against KIT regardless of secondary mutations

PKC-412 (+ Gleevec)  TKI inhibitor of several PKC isoforms but perhaps not the most relevant one for GIST (PKC theta)? Also inhibits KIT, PDGFR, VEGF, and FLT3 but perhaps not the most relevant one for GIST (PKC theta)? Also inhibits KIT, PDGFR, VEGF, and FLT3  PK interactions with Gleevec, resulting in the need for very high doses of Gleevec  Phase I trials proceeding at a slow pace Germany and US Germany and US Not currently recruiting patients Not currently recruiting patients  In vitro activity against many secondary KIT mutations and PDGFRA mutations

AMG706  AMGEN  Inhibits KIT, PDGFR, RET, and all VEGF receptors  Phase II trials closed.  Less side effects than SU11248? Continuous dosing schedule Continuous dosing schedule  Efficacy does not support a FDA filing  Results to be presented in late 2006, will not move forward in Gleevec-resistant GIST