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

What is a Clinical Trial? Health-related research study Requires ethics review (IRB) Follows a pre-defined protocol Requires informed consent No animation on this slide Only 2-4% of cancer patients participate in clinical trials

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 No animation on this slide

Risks Benefits 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 Last bullet point is “Help future patients”

Pre-Clinical Evidence of Effect in GIST Clinical Trial Phases Effect Regulatory Approval Further Study Safety 1 2 3 4 Pre-Clinical Evidence of Effect in GIST Effective in GIST Compare After Approval ? GIST Targets Drug Candidates Sometimes Combined Long Term Effects The overall picture: In general cancer drugs have taken 7-9 years to travel this path Gleevec did it in two years in GIST (but it had the benefit of CML preceding) It can be done when efficacy is high (70 % benefit versus <10% typical) and side effects are minimal. We are all looking for that next “Gleevec” Phase I First step in humans Increasing doses (cohorts) determine safe dose Evaluate route of administration Side effects 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 Phase II Further defines the safety and begins to evaluate effectiveness Approx 10% of drugs that start get approved

FDA Procedures that look like trials Compassionate access Expanded access Single patient IND Treatment use Example; Sutent Treatment Use protocol 2004 - 2005 There are several names for trials that provide access. These do not have the same inclusion/exclusion criteria. Because of potential bias, the study end points in these trials are limited. We did see some data from nilotinib compassionate access at ASCO this month.

High Patient Interest in GIST Trials Success of Gleevec

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

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

Factors Affecting Choice in Trials Eligibility Inclusion/exclusion Insurance coverage National health care issues Placebo vs. non-placebo Early perception Efficacy, side effects, etc Location Travel How far? How often? How long do you have to stay? Phase Mutation type Last bullet is Mutation Type Next slide talks about phase I dose, eligibility, logistic/financial issues 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 crossovers

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?

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 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.

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

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

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

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

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

Resistant to Gleevec 1st Line 2nd Line 3rd Line 4th Line & beyond Surgery, RFA, Ablation for limited progression 400 mg 800 mg 2nd Line Sutent 3rd Line Stivarga (regorafenib) 4th Line & beyond Clinical trials Off-label Treatment Use Trials (expanded access) Discusses what normally happens when you are resistant to Gleevec, 1st line 2nd line 3rd line 4th line & beyond (trials & off label)

Mutation Characteristics Possible Solutions Target KIT and secondary mutations Secondary mutations are frequent Exon 11 Less sensitive to imatinib Less secondary mutations? Exon 9 Insensitive to imatinib Insensitive to sunitinib Primary resistance PDGFRA Imatinib poor WT-KIT inhibitor KIT may remain activated 2/3 overexpress IGF1R Some driven by SDH mutations Wild-Type KIT exon 13 KIT exon 17 PDGFRA exon 12 PDGFRA exon 18, non D842V Rare 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 ? Little clinical data Some in-vitro data

Failure to Inhibit KIT-secondary mutations 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 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 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 In addition to the initial mutation, secondary mutations that promote resistance to Gleevec can occur.

Drugs and Names IND INN Brand Name Manufacturer STI-571 Imatinib Gleevec/Glivec Novartis SU11248 Sunitinib Sutent Pfizer AMN107 Nilotinib Tasigna Novartis Bay 43-9006 Sorafenib Nexavar Bayer BMS 354825 Dasatinib Sprycel Bristol-Myers Squibb Bay 73-4506 Regorafenib Stivarga Bayer GW786034B Pazopanib Votrient GlaxoSmithKline STA-9090 Ganetespib Synta AB1010 Masitinib AB Science OSI 906 Linsitinib OSI Pharmaceuticals LBH589 Panobinostat Novartis RAD001 Everolimus Afinitor Novartis L-001079038 Vorinostat Zolinza Merck IND – Investigational New Drug INN – International Non-proprietary Name

Drugs and Names (Cont.) Stem Meaning -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

NCCN Clinical Practice Guidelines for GIST SARC-E: Systemic agents and regimens with activity in Soft Tissue Sarcoma: GIST Imatinib Sunitinib Disease progression after Imatinib & Sunitinib Sorafenib Nilotinib Dasatinib 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

Trials Drug Category Action Stage STA9090 (I.V.) HSP90i Wide-Spectrum KIT inhibitor Phase 2 Multiple drugs (most oral) PI3Ki Downstream Phase 1 Linsitinib (OSI-906) (I.V. & oral) IGF1Ri Alternate Pathway Deciphera (oral?) KIT/PDGFRA Preclinical Imatinib + ipilimumab KIT inhibitor First-line phase 3 Masitinib Gleevec First-line Plasma level trial

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) Phase I open to all stages Expansion open to resistant GIST Serious side effects Some long-term responses seen in melanoma

Pediatric-type GIST Sutent Linitinib (OSI-906) Phase 1/2 6 years to 21 years old 6 yrs to <18 years 15 mg/m2 daily for 4 wks on/2 wks off 18 yrs to <21 yrs, 50 mg daily on 4/2 schedule Multiple trial sites (as needed) Linitinib (OSI-906) IGF1R inhibitor IGF1R overexpressed in pediatric-type GIST Phase II trial opened March, 2012 Seven sites planned SARC sponsored

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

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

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

KIT Src/Fyn/Lyn PKC-θ PI3K AKT RAS PTEN mTOR RAF-1 MEK BAD MAPK BCL-2 Imatinib-sunitinib-regorafenib-nilotinib-sorafenib pazopanib -masitinib-HSP-90 inhibitors (indirect) Src/Fyn/Lyn dasatinib PKC-θ PI3K AKT Perifosine RAS R115777-SCH66336 PTEN mTOR RAD001-CCI779 AP-23573-Rapamycin RAF-1 regorafenib MEK PKC-theta may not be correctly located in this diagram. RAS may be a potential target for NF-1 type GISTs? BAD MAPK BCL-XL BCL-2 Gentasense Proliferate Survive VEGF Avastin-sunitinib-regorafenib sorafenib-pazopanib New blood vessel growth

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

Ask Questions 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? Read

High Stakes Decision Making* Allow yourself the time to decide. Get emotional support. Make sense of controversies. Manage your decision like you manage other complex projects. Give yourself permission to experiment. Recognize your preferences. Remain vigilant about ignorance. Seek those who will teach and learn with you. Delegate. Keep records. Keep your sense of humor. This seems like really good advice. I remember that my daughter did many of these things. *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/

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/

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