September, 2006

1. September, 2006

2. Novartis video GIST-Gleevec 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 Patients and sponsors have different views of trials Sponsors The patients needs/desires are subordinate to the sponsors need/desire to get the drug/indication approved Patients Use clinical trials to survive The risks that oncology patients are willing to accept in hope of benefit, are much greater that for other areas of medicine. A patients view of risk vs. benefit is often much different than a sponsors view.Patients and sponsors have different views of trials Sponsors The patients needs/desires are subordinate to the sponsors need/desire to get the drug/indication approved Patients Use clinical trials to survive The risks that oncology patients are willing to accept in hope of benefit, are much greater that for other areas of medicine. A patients view of risk vs. benefit is often much different than a sponsors view.

7. Factors Affecting Choice in Trials 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 Some trials may have a placebo Some placebo trials have a crossover provision to receive the treatment being evaluated Some placebo trials (none in GIST or CML yet) have no provision for crossoversSome trials may have a placebo Some placebo trials have a crossover provision to receive the treatment being evaluated Some placebo trials (none in GIST or CML yet) have no provision for crossovers

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? May be good or bad. Need to balance the need for both patient and trial to have the maximum chance for success. LRG example: Talks with the sponsor (Amgen) led to Amgen�s agreement to extend their phase I trial and allow entry of this patient population into that trial. May be good or bad. Need to balance the need for both patient and trial to have the maximum chance for success. LRG example: Talks with the sponsor (Amgen) led to Amgen�s agreement to extend their phase I trial and allow entry of this patient population into that trial.

11. Failure to Inhibit KIT-secondary mutations

12. Surgery and Imatinib for GIST: Clinical Trials

13. KIT and downstream pathways are often targets in clinical trials

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

15. PKC-theta may not be correctly located in this diagram. RAS may be a potential target for NF-1 type GISTs?PKC-theta may not be correctly located in this diagram. RAS may be a potential target for NF-1 type GISTs?

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

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 PDGFR�, but not PDGFRa 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