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September, 2006

GIST Clinical Trials Life Fest 2006 Jerry Call. September, 2006. GIST-Gleevec video. Novartis 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”

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September, 2006

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  1. GIST Clinical Trials Life Fest 2006 Jerry Call September, 2006

  2. GIST-Gleevec video Novartis video

  3. 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%-Being treated by the latest treatment available • 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, 1001-1005

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

  5. High Patient Interest in GIST Trials • Success of Glivec • But also, an educated patient population • Internet-based support groups • Patients continue to join trials of new therapies for GIST • SU11248, AMG706, RAD001, PKC412, BMS-354825, AMN107, BAY 43-9006 • Early success- high expectations. GIST patients spoiled by the initial success.

  6. 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

  7. Location Travel How far? How often? 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 Factors Affecting Choice in Trials

  8. Finding Clinical Trials • http://www.liferaftgroup.org/treat_trials.html • www.clinicaltrials.gov • www.emergingmed.com • http://www.gistsupport.org/

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

  10. 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?

  11. Initial and secondary KIT mutations Ligand binding domain Exon 9-Extracellular domain Exon 11-Juxtamembrane domain Cell membrane Exon 13-Tyrosine kinase domain 1 In addition to the initial mutation, secondary mutations that promote resistance to Gleevec can occur. Kinase insert Exon 17-Tyrosine kinase domain 2 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-354825 • BAY 43-9006 • Destroy KIT protein • IPI-504 • Combinations; Gleevec + • AMN107, PKC412, etc 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 2003. 21:4342-49) Common initial mutations

  12. Surgery and Imatinib for GIST: Clinical Trials

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

  14. Effects of signaling inhibition on proliferation in GIST cell lines* 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

  15. KIT Gleevec-SU11248-BMS354825-AMG706-AMN107 PKC412-BAY 43-9006-HSP-90 inhibitors (indirect) Src/Fyn/Lyn BMS-354825 PLC PI3K JAK2 DAG PKC-θ AKT Perifosine RAS R115777-SCH66336 PTEN Ca2 CAI STAT3 mTOR RAD001-CCI779 AP-23573-Rapamycin RAF-1 BAY 43-9006 MEK BAD Survive-grow STAT1 MAPK BCL-XL BCL-2 Gentasense Proliferate Survive VEGF Avastin-Su11248-BAY 43-9006 PKC412-AMG706 New blood vessel growth

  16. Sutent BAY 43-9006 BMS-354825 IPI-504 CCI-779 (complete) AMG706 (complete) AMN107 + Gleevec RAD001 + Gleevec PKC412 + Gleevec Perifosine + Gleevec Genasense + Gleevec Drugs in GIST trials • Future Trials? • Avastin + Gleevec • OSI-930

  17. Sarcoma Trials that allow GIST • Doxorubicin + Flavopiridol • Phase I-MSKCC • Flavopiridol is an inhibitor of the cell cycle and an inhibitor of transcription • FR901228 • 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.

  18. Drug Targets

  19. Sutent • Pfizer Oncology • Other names • SU11248 (sometimes appears as SU011248) • Sugen • 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? • Available in other countries via a “Treatment use protocol” administered by EmergingMed (1-800-620-6104) • 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.

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

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

  22. AMN107 (+ Gleevec) • Phase I/II GIST trials underway • US • Boston • Philadelphia • Europe • Leuven, Belgium • Lyon, France • Berlin, Germany • Milan, 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?

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

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

  25. BMS-354825 • 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

  26. Perifosine and Genasense • Perifosine • Small molecule inhibitor of AKT. • AKT is an anti-apoptosis protein. Inhibition of AKT may enhance therapy. • 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. • Phase II trial at MDACC is accruing patients. The trial combines Gleevec + Genasense. Four more trial sites are pending activation.

  27. BAY 43-9006 • 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) • 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

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

  29. 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? OR • Will the broad-activity contribute to anti-tumor effects? • In theory works against KIT regardless of secondary mutations

  30. 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 • 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 • Not currently recruiting patients • In vitro activity against many secondary KIT mutations and PDGFRA mutations

  31. AMG706 • AMGEN • Inhibits KIT, PDGFR, RET, and all VEGF receptors • Phase II trials closed. • Less side effects than SU11248? • 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

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