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MEASURING CLINICAL EFFICACY IN PHASE II TRIALS

MEASURING CLINICAL EFFICACY IN PHASE II TRIALS. Response: Karnofsky, WHO, RECIST Event rate: progression free/survival Time to event: progression/survival Functional imaging Mutational analysis-biomarkers. Endpoints Used in SWOG Phase II Trials.

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MEASURING CLINICAL EFFICACY IN PHASE II TRIALS

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  1. MEASURING CLINICAL EFFICACY IN PHASE II TRIALS • Response: Karnofsky, WHO, RECIST • Event rate: progression free/survival • Time to event: progression/survival • Functional imaging • Mutational analysis-biomarkers

  2. Endpoints Used in SWOG Phase II Trials • 86 Phase II studies numbering from S9902-S0517

  3. Does Source of Drug Affect Endpoint Selection in SWOG Phase II Trials?

  4. Clinical Benefit in Sarcoma “RECIST or survival in untreated patients is the gold standard”– Scott Saxman,M.D. “It’s difficult to show clinical benefit when the data are ‘clouded’ with subtypes with variable response.” – SARC investigators “Most of the commonly used agents are ‘ancient warriors-we need new drugs’.”–Ernie Borden, MD

  5. Is Survival an Appropriate Endpoint in Phase II? • Affected by subsequent therapy • Affected by factors unrelated to the disease • age • comorbidities • Long survivals seen in indolent disease Survival - Phase II trial of 9NC Chugh et al, JCO 23:3597, 2005

  6. 2 A/I MRI/CT FDG PET Surgery No progression N=33 Biopsy MRI/CT FDG PET 2 A/I MRI/CT FDG PET N=41 Progression Surgery N=8 PET but not Recist agrees with histologic response in Sarcomas • ASCO 05-Schuetze, Eary, Conrad

  7. Tumor Response After 4 Cycles

  8. “You should desist from using RECIST, at least in GIST ? in sarcoma ? Benjamin, CTOS, 2004 Baker, ASCO, 2005

  9. Progression free rate 4 months 6 months 44% 36.% 1 14%at 6 mos. Progression-free Survival ABT-510 30% at 4 mos Inactive 1 Van Glabbeke M et al. Eur J Cancer. 2002;38:543-549.

  10. Patient Outcome in the SARC Gleevec Trial Compared to baseline, the patient’s disease status at each two-month evaluation is one of CR = complete response PR = partial response SD = stable disease PD = progressive disease or death “Response” = {CR/PR @ month 2} or {SD @ month 2 + CR/PR/SD @ month 4}

  11. PRACTICAL ADVANTAGES OF THE BAYESIAN DESIGN The hierarchical model allows data from each subtype to provide information about parameters in all other subtypes It avoids two undesirable approaches, conducting : - One trial, assuming one common parameter, ignoring the subtypes, or - Separate trials that ignore each others’ data User-friendly front ends greatly facilitate trial conduct

  12. 95% Posterior Credible Intervals by Histologic Subtype 0.3 q = Pr( Response )

  13. 65 yo man with malignant fibrous histiocytoma Pre-Gleevec H & E 2 weeks on Rx cKIT

  14. 74 yo man with myofibroblastic sarcoma Pre-Gleevec H &. E 8 weeks on Rx cKIT

  15. ABT-510 Trial Design • Randomized, open-label, multi-center • 20 mg SC QD vs 100 mg SC BID(200 mg/d) • 88 patients total • 28-day cycles until evidence of progression • Primary endpoint: • Progression-free survival • Secondary endpoints: • Response rate • Overall survival • Performance status

  16. Eligibility Criteria • High grade, locally advanced/metastatic STS • No more than 2 prior cytotoxic regimens • Adequate hepatic, renal, and bone marrow function • No brain mets • No prior serious bleeding episodes; no anticoagulants

  17. No. of Subjects 20 mg QD 100 mg BID Total 42 46 88 Age (years) <40 5 (12%) 10 (22%) 15 (17%) 40 - 60 21 (50%) 22 (48%) 43 (49%) >60 16 (38%) 14 (30%) 30 (34%) Gender Men 18 (43%) 26 (57%) 44 (50%) Women 24 (57%) 20 (43%) 44 (50%) ECOG PerformanceStatus 0 25 (60%) 19 (41%) 44 (50%) 1 17 (40%) 27 (59%) 44 (50%) Prior Cytotoxic Chemotherapy Yes 27 (64%) 37 (80%) 64 (73%) No 15 (36%) 9 (20%) 24 (27%) Patient Demographics

  18. Tumor Subtypes Subtype# Pts (%) Leiomyosarcoma 18 (20) Liposarcoma 17 (19) Spindle cell sarcoma NOS 9 (10) Synovial sarcoma 6 (7) Alveolar soft part sarcoma 5 (6) Fibrosarcoma 5 (6) Malignant fibrous histiocytoma 5 (6) Angiosarcoma 4 (5) Malignant peripheral nerve sheath tumor 4 (5) Other 15 (17)

  19. Progression-free Survival Progression Free Rate Dose 4 Month 6 month 20 mg QD 49% 42% 44% 100 mg BID 36% 100 mg BID ABT-510 20 mg QD ABT-510 Historical Control 1 14%

  20. Progression-free Survival No Prior Chemotherapy Prior Chemotherapy Historical Control 1 14% *

  21. PFS at Boston and Ann Arbor Ann Arbor Boston

  22. PFS EFFICACY CONSIDERATIONS • INVESTIGATOR SELECTION BIAS patient recruitment interpretation of progression influence of patients clinician vs. review radiologist • PFS relies in part on RECIST • PROGRESSION FREE SURVIVAL NEEDS VALIDATION AND REFINEMENT

  23. Erice, Sicily

  24. Anatomy of the Ideal Phase II Endpoint • Endpoint is measurable in the Majority of the patient population of interest • Endpoint is generally acceptable as a marker for treatment Activity • Endpoint measurement is available at early Timepoints in Treatment • Endpoint measurement is Easy and Reproducible

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