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GIST Clinical Trials Life Fest 2006 Jerry Call September, 2006 Novartis video GIST-Gleevec video 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 Trial phases Phase I Phase II Further defines the safety and begins to evaluate effectiveness Phase III First step in humans Increasing doses (cohorts) determine safe dose Evaluate route of administration Side effects 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 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, BMS354825, AMN107, BAY 43-9006 Early success- high expectations. GIST patients spoiled by the initial success. 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 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. nonplacebo Early perception Efficacy, side effects, etc Finding Clinical Trials http://www.liferaftgroup.org/treat_trials.html www.clinicaltrials.gov www.emergingmed.com http://www.gistsupport.org/ 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 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? Failure to Inhibit KIT-secondary mutations Initial and secondary KIT mutations Ligand binding domain 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 Cell membrane Possible Solutions: •Different KIT inhibitor with activity against both the primary and secondary mutation. Possibilities include: •Sutent (approved in US) Exon 9-Extracellular domain •AMG706 (closed) Exon 11-Juxtamembrane domain •BMS-354825 •BAY 43-9006 Exon 13-Tyrosine kinase domain 1 In addition to the initial mutation, secondary mutations that promote resistance to Gleevec can occur. Kinase insert •Destroy KIT protein •IPI-504 •Combinations; Gleevec + Exon 17-Tyrosine kinase domain 2 •AMN107, PKC412, etc Surgery and Imatinib for GIST: Clinical Trials Trial Description Phase 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 = 380 EORTC Soft Tissue and Bone Sarcoma Group End points: overall, recurrence-free survival; risk stratification/randomization after complete GIST resection to imatinib or no treatment for 2 years; projected enrollment = 400 Scandinavian Sarcoma Group Trial SSGXVIII End points: recurrence-free survival, safety, overall survival; imatinib administered postoperatively for 12 or 36 months; projected enrollment = 80 Phase II Study of Neoadjuvant and Adjuvant Imatinib Mesylate in Patients With Primary or Recurrent Potentially Resectable Malignant GIST (RTOGS0132 End 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 = 63 GIST 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 trials KIT PKC-θ AKT/mTOR MAPK PLC gamma Jak/Stat 3 Survive-grow PI3K - a central player – But no drug yet! PI3K Survive Proliferate Effects of signaling inhibition on proliferation in GIST cell lines* Inhibition target GIST882 Exon 13 (k642E) GIST430 Exon 11 (V560D)+ Exon 13 (V654A) GIST48 Exon 11+ Exon 17 (D820A) PI3-K 45 38 28 MEK/MAPK 48 67 74 mTOR 79 62 80 PLC-gamma 90 89 99 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 KIT Gleevec-SU11248-BMS354825-AMG706-AMN107 PKC412-BAY 43-9006-HSP-90 inhibitors (indirect) Src/Fyn/Lyn BMS-354825 PLC JAK2 PI3K DAG AKT PKC-θ PTEN Perifosine Ca2 RAS R115777-SCH66336 CAI STAT3 mTOR RAF-1 RAD001-CCI779 AP-23573-Rapamycin BAY 43-9006 MEK Survive-grow BAD STAT1 BCL-2 BCL-XL Gentasense VEGF Avastin-Su11248-BAY 43-9006 PKC412-AMG706 Survive New blood vessel growth MAPK Proliferate 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 Future Trials? •Avastin + Gleevec •OSI-930 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. Drug Targets Gleevec KIT PDGFRα PDGFRß Bcr/abl Sutent KIT PDGFRα PDGFRß VEGFR FLT3 AMG706 KIT PDGFRα PDGFRß VEGFR RET BAY439006 KIT PDGFRß VEGFR FLT3 AMN107 KIT PDGFRα PDGFRß Bcr/abl BMS354825 KIT PDGFRα ? Bcr/abl SCR PKC412 KIT PDGFRα PDGFRß VEGFR PKC FLT3 RAD001 mTOR CCI-779 mTOR AP23573 mTOR Rapamycin mTOR Perifosine AKT Genasense Bcl-2 IPI-504 HSP90 KIT AKT VEGF ? 17DMAG HSP90 KIT AKT VEGF ? OSI930 KIT RET ? VEGFR ? Sutent Pfizer Oncology Other names 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. SU11248 (sometimes appears as SU011248) Sugen Sunitinib malate (the generic name) 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. 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 Sutent concerns Increased activity/growth during the “off cycle”? Side effects Heart toxicity? Is this concern overrated? Hypertension Increased fatigue 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? 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 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 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 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. 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 PDGFRß, but not PDGFRα 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 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? Next generation may include oral drugs 17DMAG IPI-504 Infinity Pharmaceuticals phase I trial is open at Dana-Farber (no results yet) CNF20204 (Conforma) The stronger KIT activation, the better the drug works 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 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 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