September, 2006GIST Clinical TrialsLife Fest 2006Jerry Call

Novartis video

GIST-Gleevec video

Why do Patients Participate in Trials*?89%-Obtaining possible benefit very important17%-Helping future cancer patients/treatmentsOther factors cited as very important66%-Trust in doctor66%-Being treated by the latest treatment available61%-Better standard of care and closer follow-up71% 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

Trial phasesPhase IFirst step in humansIncreasing doses (cohorts) determine safe doseEvaluate route of administrationSide effectsPhase IIFurther defines the safety and begins to evaluate effectivenessPhase IIICompare a new agent with the current standard treatment.Randomized to groupsPhase IVUsually take place after the treatment is approvedFurther evaluate long-term safety and effectiveness

High Patient Interest in GIST TrialsSuccess of Glivec But also, an educated patient populationInternet-based support groupsPatients continue to join trials of new therapies for GISTSU11248, AMG706, RAD001, PKC412, BMS-354825, AMN107, BAY 43-9006Early success- high expectations. GIST patients spoiled by the initial success.

Patients use clinical trials to surviveAccess to the latest drugsMedical team that is more familiar with GISTMedical treatment and monitoring are usually betterClinical trials move GIST research forwardMay be a last resort/last chance

Factors Affecting Choice in TrialsLocationTravelHow far?How often?How long do you have to say?PhaseEligibilityInclusion/exclusionInsurance coverageNational health care issuesPlacebo vs. non-placeboEarly perceptionEfficacy, side effects, etc

Finding Clinical Trialshttp://www.liferaftgroup.org/treat_trials.html

www.clinicaltrials.gov

www.emergingmed.com

http://www.gistsupport.org/

Navigating Clinical TrialsPhase l: Starting at the right dosage levelDetermining EligibilityLogistic and Financial IssuesWhere is the trial site?Am I eligible to go there?How often to I have to go there?For how long?At what costs?

Previous Treatment ExclusionsParticipation in some trials may prevent entry into other trialsExample: 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 mutationsPossible Solutions:Different KIT inhibitor with activity against both the primary and secondary mutation. Possibilities include:Sutent (approved in US)AMG706 (closed)BMS-354825BAY 43-9006Destroy KIT proteinIPI-504Combinations; Gleevec +AMN107, PKC412, etcPrior 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

Surgery and Imatinib for GIST: Clinical Trials

TrialDescriptionPhase 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 = 380EORTC Soft Tissue and Bone Sarcoma GroupEnd points: overall, recurrence-free survival; risk stratification/randomization after complete GIST resection to imatinib or no treatment for 2 years; projected enrollment = 400Scandinavian Sarcoma Group Trial SSGXVIIIEnd points: recurrence-free survival, safety, overall survival; imatinib administered postoperatively for 12 or 36 months; projected enrollment = 80Phase II Study of Neoadjuvant and Adjuvant Imatinib Mesylate in Patients With Primary or Recurrent Potentially Resectable Malignant GIST (RTOG-S0132End 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 = 63GIST 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.

KIT and downstream pathways are often targets in clinical trialsAKT/mTORMAPKKITPI3KJak/Stat 3Survive-growSurviveProliferatePLC gammaPI3K - a central player But no drug yet!PKC-

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

Inhibition targetGIST882Exon 13 (k642E)

GIST430Exon 11 (V560D)+Exon 13 (V654A)GIST48Exon 11+Exon 17(D820A)

PI3-K453828MEK/MAPK486774mTOR796280PLC-gamma908999

KITGleevec-SU11248-BMS354825-AMG706-AMN107PKC412-BAY 43-9006-HSP-90 inhibitors (indirect)PI3KAKTPerifosine mTORRAD001-CCI779 AP-23573-Rapamycin

DAGPKC-RASR115777-SCH66336 RAF-1BAY 43-9006MEKMAPKJAK2STAT3PTENBCL-2GentasensePLCSTAT1BCL-XLBADCa2CAISrc/Fyn/LynBMS-354825Survive-growSurviveProliferateVEGFAvastin-Su11248-BAY 43-9006PKC412-AMG706New blood vessel growth

Drugs in GIST trialsSutentBAY 43-9006BMS-354825IPI-504CCI-779 (complete)AMG706 (complete)AMN107 + GleevecRAD001 + GleevecPKC412 + GleevecPerifosine + GleevecGenasense + GleevecFuture Trials?Avastin + GleevecOSI-930

Sarcoma Trials that allow GISTDoxorubicin + FlavopiridolPhase I-MSKCCFlavopiridol is an inhibitor of the cell cycle and an inhibitor of transcription FR901228 Phase IIBelongs 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

SutentPfizer OncologyOther namesSU11248 (sometimes appears as SU011248)SugenSunitinib malate (the generic name)TKI-KIT, PDGFR, FLT-3, VEGFOnly drug with proven ability against Gleevec resistant GISTApproved 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 closedNew 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-2Gleevec-resistant GIST highly sensitive to SU11248KITExon 9Wild-type for KIT & PDGFRASecondary exon 13 or 14Gleevec-resistant GIST less sensitive to SU11248KIT exon 11KIT secondary exon 17, exon 18 mutations

Sutent concerns

Increased activity/growth during the off cycle?Side effectsHeart toxicity? Is this concern overrated?HypertensionIncreased fatigue

AMN107 (+ Gleevec)Phase I/II GIST trials underwayUSBoston Philadelphia EuropeLeuven, BelgiumLyon, FranceBerlin, 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 mutationsCompassionate useRegistration trial-Fall of 2006?

mTOR as a targetmTOR is a downstream protein in the KIT and PDGFR pathways

Three mechanisms of anti-tumor activity:Tumor cell shrinkageCell cycle arrest at late G1Anti-angiogenesis

mTOR inhibitorsRAD001In phase I trials in combination with Gleevec. RAD001 is approved for transplant patients in many European countriesAP23573Ongoing sarcoma trials. GIST?CCI-779Ongoing phase II GIST trial as a single agentRapamycin (Rapamune)Earliest mTOR inhibitor (least advanced?) Approved for transplant patients in many countries

BMS-354825TKI inhibitor of Bcr-Abl, KIT, PDGFRA, SrcActivity against both the inactive and active kinase conformations of Bcr-Abl (and also KIT?)Effective against 14 of 15 Gleevec resistant CML mutationsNot effected by p-glycoprotein MDR efflux pump300 to 650 times more potent than Gleevec against Gleevec resistant CML linesLess effective for KIT? For GIST, may need to be dosed near the MTD

Perifosine and GenasensePerifosineSmall molecule inhibitor of AKT.AKT is an anti-apoptosis protein. Inhibition of AKT may enhance therapy.Phase II trial combining Gleevec + Perifosine at MDACC.GenasenseAn 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.

BAY 43-9006Known as a RAF kinase inhibitor, but also a powerful KIT inhibitor, as well as VEGFR2RAF is part of the MAPK downstream pathway in KIT and PDGFRInhibition of multiple kinases may be more effective (KIT, RAF, VEGF)Inhibits PDGFR, but not PDGFRSeveral responses in Imatinib-resistant GIST have been reportedFDA approved for advanced kidney cancerPhase II GIST trials at Univ. of Chicago and other centers

IPI-504HSP90 inhibitors17AAG (poor drug-like qualities)Would participation in a trial of 17AAG preclude entry into a trial with one of the newer drugs?17DMAGIPI-504 Infinity Pharmaceuticals phase I trial is open at Dana-Farber (no results yet)Next generation may include oral drugsCNF20204 (Conforma)The stronger KIT activation, the better the drug works

HSP90The HSP90 protein helps to fold proteins into their proper conformation and protects client proteinsImproperly folded proteins are not functional and are destroyed within the cellHSP90 inhibitors degrade KIT and other proteins in GISTWill the lack of specificity contribute to side effects?ORWill 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 isoformsbut perhaps not the most relevant one for GIST (PKC theta)? Also inhibits KIT, PDGFR, VEGF, and FLT3PK interactions with Gleevec, resulting in the need for very high doses of GleevecPhase I trials proceeding at a slow paceGermany and USNot currently recruiting patientsIn vitro activity against many secondary KIT mutations and PDGFRA mutations

AMG706AMGENInhibits KIT, PDGFR, RET, and all VEGF receptorsPhase II trials closed.Less side effects than SU11248?Continuous dosing scheduleEfficacy does not support a FDA filingResults to be presented in late 2006, will not move forward in Gleevec-resistant GIST

Patients and sponsors have different views of trialsSponsorsThe patients needs/desires are subordinate to the sponsors need/desire to get the drug/indication approvedPatientsUse clinical trials to surviveThe 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.Some trials may have a placeboSome placebo trials have a crossover provision to receive the treatment being evaluatedSome placebo trials (none in GIST or CML yet) have no provision for crossoversMay 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 Amgens agreement to extend their phase I trial and allow entry of this patient population into that trial.

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