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Clinical Trials Explained and Explored

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. Only 2-4% of cancer patients participate in clinical trials.

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Clinical Trials Explained and Explored

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  1. Clinical TrialsExplained and Explored Presented By: Jerry Call March 11, 2013

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

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

  5. Clinical Trial Phases Further Study GIST Targets ? Sometimes Combined After Approval 3 2 Pre-Clinical Evidence of Effect in GIST 4 Effective in GIST 1 Long Term Effects Safety Effect Compare Drug Candidates Regulatory Approval • 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 • PhaseII • Furtherdefines the safety and begins to evaluate effectiveness • Approx 10% of drugs that start get approved

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

  7. High Patient Interest in GIST Trials Success of Gleevec

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

  9. 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

  10. 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

  11. 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?

  12. 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

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

  14. Recently Diagnosed • Neoadjuvant 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

  15. 1st line Trials • Masitinib • Phase III • USA • Florida • Ohio • Crenolanib (D842V mutation only) • Fox Chase • OHSU • Dasatinib (Sprycel) • Recently closed

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

  17. 2nd Line Trials • Sutent + TH-302 • Masitinibvs Sutent • Phase 3 trial recently opened; 50 sites. 2nd line means “After Failure of Gleevec”

  18. Resistant to Gleevec • 1st Line • 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)

  19. Target KIT and secondarymutations • 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

  20. Failure to Inhibit KIT-secondary mutations 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 • 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

  21. 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 SorafenibNexavar Bayer BMS 354825 Dasatinib Sprycel Bristol-Myers Squibb Bay 73-4506 RegorafenibStivarga Bayer GW786034BPazopanibVotrientGlaxoSmithKline STA-9090 GanetespibSynta AB1010 Masitinib AB Science OSI 906 Linsitinib OSI Pharmaceuticals LBH589Panobinostat Novartis RAD001 EverolimusAfinitorNovartis L-001079038VorinostatZolinzaMerck IND – Investigational New Drug INN – International Non-proprietary Name

  22. 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

  23. 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

  24. Trials

  25. 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

  26. Pediatric-type GIST • Sutent • 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

  27. 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)

  28. Trials by Genotype • Pediatric-type GIST • 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

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

  30. KIT 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 BAD MAPK BCL-XL BCL-2 Gentasense Proliferate Survive VEGF Avastin-sunitinib-regorafenib sorafenib-pazopanib New blood vessel growth

  31. 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” JaapVerweij, 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

  32. 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?

  33. 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. *Top Ten Decision Lessons from the Community Breast Health Project (CBHP) in Palo Alto, CABy Jeff Belkora, September 1997 http://www.guidesmith.org/top-ten-lessons/

  34. 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/

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

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