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 86 Phase II studies numbering from S9902-S0517

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

Clinical Benefit in Sarcoma “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 “ RECIST or survival in untreated patients is the gold standard”– Scott Saxman,M.D.

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

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

Tumor Response After 4 Cycles RECIST(anatomic) < 10% viable tumor(pathology) Response6(18%)3 Stable246 Progression3(9%) 1 rr=10/33(30%) PET(functional) < 10% viable tumor Response17(52%)7 No response111 Progression4(12%)1

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

Progression-free Survival 1 Van Glabbeke M et al. Eur J Cancer. 2002;38: %44% 6 months4 months Progression free rate 1 14%at 6 mos. ABT-510 –Inactive 30% at 4 mos

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” = month 2} or month 2 + month 4}

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

 = Pr( Response ) 95% Posterior Credible Intervals by Histologic Subtype 0.3

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

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

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 ABT-510 Trial Design

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

24 (27%)9 (20%)15 (36%) No 64 (73%)37 (80%)27 (64%) Yes 43 (49%)22 (48%)21 (50%) Prior Cytotoxic Chemotherapy 44 (50%)27 (59%)17 (40%) 1 44 (50%)19 (41%)25 (60%) 0 ECOG Performance Status 44 (50%)20 (43%)24 (57%) Women 44 (50%)26 (57%)18 (43%) Men Gender 30 (34%)14 (30%)16 (38%) >60 15 (17%)10 (22%)5 (12%) <40 Age (years) No. of Subjects Total100 mg BID20 mg QD Patient Demographics

Tumor Subtypes Subtype # Pts (%) Leiomyosarcoma18 (20) Liposarcoma17 (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)

Progression-free Survival 20 mg QD ABT mg BID ABT-510 Historical Control 1 14% 36% 44% 100 mg BID 42%49%20 mg QD 6 month4 MonthDose Progression Free Rate

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

PFS at Boston and Ann Arbor –Ann Arbor –Boston

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

Erice, Sicily

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