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Clinical Trials Explained and Explored Presented By: Jerry Call March 11, 2013

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What is a Clinical Trial? Health-related research study Requires ethics review (IRB) Follows a pre-defined protocol Requires informed consent Only 2-4% of cancer patients participate in clinical trials

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Why do Patients Participate in Trials*? 89%-Obtaining possible benefit very important 17%-Helping future cancer patients/treatments Other factors cited as very important o 66%-Trust in doctor o 66%-Being treated by the latest treatment available o 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

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May not be effective Side effects Additional testing, time and travel (travel expenses) Some costs may not be covered by insurance Option to access treatment after standard treatments fail Receive treatment at a major GIST trial center Help future patients BenefitsRisks

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Clinical Trial Phases Approx 10% of drugs that start get approved 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 o Usually take place after the treatment is approved o Further evaluate long-term safety and effectiveness Phase I o First step in humans o Increasing doses (cohorts) determine safe dose o Evaluate route of administration o Side effects

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FDA Procedures that look like trials Compassionate access Expanded access Single patient IND Treatment use o Example; Sutent Treatment Use protocol 2004 - 2005

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High Patient Interest in GIST Trials Success of Gleevec

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GIST Survival-Historical vs. Current Therapy* *Lancet 2004; 1127-134

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High Patient Interest in GIST Trials Success of Gleevec Educated patient population o Internet-based support groups Patients continue to join trials of new therapies for GIST o But at a declining rate? o Early success- high expectations o GIST patients spoiled by the initial success Off-Label drug access

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

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

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Previous Treatment Exclusions Participation in some trials may prevent entry into other trials Examples Treatment with an HSP90 inhibitor may exclude you from trials with a different HSP90 inhibitor Treatment with a VEGFR inhibitor may prevent treatment with a second VEGFR/KIT inhibitor May require some planning to sequence trials

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Treatment Phases Recently Diagnosed Stable Disease 2 nd Line 3 rd Line and beyond

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Recently Diagnosed Neoadjuvant trials o Does drug therapy before surgery make surgery easier? Adjuvant trials o Does Gleevec after surgery prevent or delay a recurrence of GIST First Line Trials o Is another drug better than Gleevec when given to new patients? o Plasma levels? o Is another drug more tolerable? o By genotype

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1 st line Trials Masitinib o Phase III o USA Florida Ohio Crenolanib (D842V mutation only) o Fox Chase o OHSU Dasatinib (Sprycel) o Recently closed

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Stable Disease Surgery for metastatic GIST that is stable? Difficult to randomize patients to surgery

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2 nd Line Trials Sutent + TH-302 Masitinib vs Sutent o Phase 3 trial recently opened; 50 sites. 2nd line means After Failure of Gleevec

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Resistant to Gleevec 1 st Line o Surgery, RFA, Ablation for limited progression o 400 mg800 mg 2 nd Line o Sutent 3 rd Line o Stivarga (regorafenib) 4th Line & beyond o Clinical trials o Off-label o Treatment Use Trials (expanded access)

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Target KIT and secondary mutations Higher dose IM or Sutent Much not known CP-868,596 (ph II trial) Dasatinib? HSP90 or PI3K inhibitor Potent WT KIT inhibitors IGF-1R SDH ? MutationCharacteristicsPossible Solutions Little clinical data Some in-vitro data

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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) Stivarga (approved in US) Dovitinib DCC-2618 (Deciphera) Destroy KIT protein STA-9090, AUY922 Combinations; Gleevec + AT13387, BKM120, 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 2003. 21:4342-49) 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

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INDINNBrand NameManufacturer STI-571ImatinibGleevec/GlivecNovartis SU11248SunitinibSutentPfizer AMN107NilotinibTasignaNovartis Bay 43-9006SorafenibNexavarBayer BMS 354825DasatinibSprycelBristol-Myers Squibb Bay 73-4506RegorafenibStivargaBayer GW786034B PazopanibVotrientGlaxoSmithKline STA-9090GanetespibSynta AB1010MasitinibAB Science OSI 906LinsitinibOSI Pharmaceuticals LBH589PanobinostatNovartis RAD001EverolimusAfinitorNovartis L-001079038VorinostatZolinzaMerck Drugs and Names IND Investigational New Drug INN International Non-proprietary Name

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Drugs and Names (Cont.) StemMeaning -tinib = Tyrosine Kinase Inhibitor (imatinib, sunitinib, regorafenib) -mab = Monoclonal Antibody (ipilimumab) -rolimus = Rapamycin Derivatives (mTOR inhibitors) (everolimus) -inostat = Histone Deacetylase (HDAC) Inhibitors (vorinostat) World Health Organization (WHO) International Nonproprietary Names (INN) for pharmaceutical substances, Stem Book 2009 United States Adopted Names (USAN) are unique nonproprietary names assigned to pharmaceuticals marketed in the United States. Each name is assigned by the USAN Council, which is co-sponsored by the American Medical Association (AMA), the United States Pharmacopeial Convention (USP), and the American Pharmacists Association (APhA). As a general rule, the application for a USAN should be forwarded to the USAN Council after the Investigational New Drug (IND) has been approved by the FDA and clinical trials have begun. Reference

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NCCN Clinical Practice Guidelines for GIST NCCN Guidelines Version 2.2012 5/24/2012 - Soft Tissue Sarcoma - Discussion - Gastrointestinal Stromal Tumors - Progressive Disease: Page MS-30 "Any patients who has progression of GIST despite prior therapy or who has a recurrence, regardless of presentation, should be considered a candidate for enrollment in a clinical trial, if an appropriate trial is available." Reference SARC-E: Systemic agents and regimens with activity in Soft Tissue Sarcoma: GIST Imatinib Sunitinib Disease progression after Imatinib & Sunitinib Sorafenib Nilotinib Dasatinib

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Trials DrugCategoryActionStage STA9090 (I.V.) HSP90iWide-Spectrum KIT inhibitor Phase 2 Multiple drugs (most oral) PI3KiDownstreamPhase 1 Linsitinib (OSI-906) Multiple drugs (I.V. & oral) IGF1RiAlternate Pathway Phase 2 Deciphera (oral?) KIT/PDGFRAWide-Spectrum KIT inhibitor Preclinical Imatinib + ipilimumabKIT/PDGFRAKIT inhibitorFirst-line phase 3 MasitinibKIT/PDGFRAKIT inhibitorFirst-line phase 3 GleevecKIT/PDGFRAKIT inhibitorFirst-line Plasma level trial

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Immunotherapy Dasatinib + ipilimumab (Yervoy) (Memorial Sloan-Kettering (New York) Imatinib + ipilimumab MD Anderson (Houston) Ipilimumab is approved for melanoma Blocks CTLA-4 receptor on T-cells (enhances T-cell activity) Imatinib positive effect on immunotherapy via inhibition of IDO. IDO inhibits cd8+ T-cells Phase I plus expansion (MSKCC) o Phase I open to all stages o Expansion open to resistant GIST

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Pediatric-type GIST Sutent o Phase 1/2 o 6 years to 21 years old o 6 yrs to

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GIST Stages Gleevec/Sutent resistance (3 rd line and beyond) Adjuvant Gleevec trials First-line trials Neo-adjuvant Gleevec Second-line trials Other o Resistant to 400 mg Gleevec o Palliative o Surgery (stable mets)

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Trials by Genotype Pediatric-type GIST o IGF1R - Linsitinib o SDH no trials yet PDGFRA o D842V - Crenolanib o IMC-3G3 monoclonal antibody PDGFRA mutation arm No PDGFRA mutation arm (KIT mutation & wildtype GIST) Exon 9 o Korean Study 400 mg IM for 4 wks, 600 mg for 4 wks, then 800 mg IM

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AKT/mTOR MAPK KIT PI3K Jak/Stat 3 Survive-grow SurviveProliferate PLC gamma PI3K Drugs in phase 1 trials KIT and downstream Pathways are often targets in clinical trials PKC-

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KIT Imatinib-sunitinib-regorafenib-nilotinib-sorafenib pazopanib -masitinib-HSP-90 inhibitors (indirect) PI3K AKT Perifosine mTOR RAD001-CCI779 AP-23573-Rapamycin PKC- RAS R115777-SCH66336 RAF-1 regorafenib MEK MAPK PTEN BCL-2 Gentasense BCL-X L BAD Src/Fyn/Lyn dasatinib Survive Proliferate VEGF Avastin-sunitinib-regorafenib sorafenib-pazopanib New blood vessel growth

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General Trial Issues Right now there are limited Phase 3 Options Off Label use not formally reported outside clinical trial setting Personalized GIST Treatment o GIST may be 10 diseases Jaap Verweij, MD ASCO 2011 o Volunteer pool more critical with multiple smaller groups Clinician awareness o Patients need to ask what trials are available Trials without mutant KIT/PDGFRA Coverage Washout periods

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How does the new treatment work differently for you? Which trial offers the best chance of survival? What are the chances it will benefit you? What are the options if the trial does not work for you? Will this trial limit future options? How much time do you have to decide? If phase 1, will the dose be therapeutic? Ask Questions

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High Stakes Decision Making* 1.Allow yourself the time to decide. 2.Get emotional support. 3.Make sense of controversies. 4.Manage your decision like you manage other complex projects. 5.Give yourself permission to experiment. 6.Recognize your preferences. 7.Remain vigilant about ignorance. Seek those who will teach and learn with you. 8.Delegate. 9.Keep records. 10.Keep your sense of humor. *Top Ten Decision Lessons from the Community Breast Health Project (CBHP) in Palo Alto, CA By Jeff Belkora, September 1997 http://www.guidesmith.org/top-ten-lessons /

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Finding Clinical Trials GIST centers, trial coordinators, doctors, websites http://www.liferaftgroup.org/treat_trials.html www.clinicaltrials.gov www.emergingmed.com http://www.gistsupport.org/

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Help Understanding Trials Jim Hughes LRG Clinical Trials Coordinator 847 866-8360 Jerry Call LRG Science Director 303 835-1745