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

0

5

10

15

20

25

30

Primary Endpoints

RECIST Response

Marker Response

HematologicResponse

Pathologic CR

Progression Rate

Survival

Feasibility

• 86 Phase II studies numbering from S9902-S0517

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

0

5

10

15

20

25

NCI n=37 Commercial n=33

RECIST Response Marker Response Hematologic Response

Pathologic CR Progression Survival

Feasibility

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

BiopsyMRI/CTFDG PET

MRI/CTFDG PET

MRI/CTFDG PETSurgery

2 A/I

2 A/I

Progression Surgery

No progression

N=41

N=33

N=8

–ASCO 05-Schuetze, Eary, Conrad

Tumor Response After 4 Cycles

RECIST(anatomic) < 10% viable tumor(pathology)

Response 6(18%) 3

Stable 24 6

Progression 3(9%)1

rr=10/33(30%)

PET(functional) < 10% viable tumor

Response 17(52%) 7

No response 11 1

Progression 4(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;38:543-549.1 Van Glabbeke M et al. Eur J Cancer. 2002;38:543-549.

36.%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” = {CR/PR @ month 2} or

{SD @ month 2 + CR/PR/SD @ month 4}

PRACTICAL ADVANTAGES OF THE BAYESIAN DESIGN

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

0.0 0.2 0.4 0.6 0.8 1.0

-12

-10

-8-6

-4-2

0.0 0.2 0.4 0.6 0.8 1.0

Angiosarcoma

Ewings

Fibrosarcoma

Leiomyosarcoma

Liposarcoma

MFH

Osteosarcoma

PNS

Rhabdomyosarcoma

Synovial

Desmoid

= 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 High grade, locally advanced/metastatic STSSTS

• No more than 2 prior cytotoxic regimensNo more than 2 prior cytotoxic regimens

• Adequate hepatic, renal, and bone marrow Adequate hepatic, renal, and bone marrow functionfunction

• No brain metsNo brain mets

• No prior serious bleeding episodes; no No prior serious bleeding episodes; no anticoagulantsanticoagulants

Eligibility Criteria

24 (27%)9 (20%)15 (36%) No

64 (73%)37 (80%)27 (64%) Yes

43 (49%)22 (48%)21 (50%)40 - 60

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)

884642No. of SubjectsTotal100 mg BID20 mg QD

Patient Demographics

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)

Progression-free Survival

20 mg QD ABT-510100 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 ChemotherapyPrior

ChemotherapyHistorical 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