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Resampling phase III data to assess phase II trial designs and endpoints

Manish R Sharma1, Theodore G Karrison, Yuyan Jin

  • 1Departments of Medicine and Health Studies, University of Chicago, Chicago, Illinois, USA.

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
|January 31, 2012
PubMed
Abstract

Insights

For growth inhibitory agents in metastatic renal cancer, a randomized phase II trial using the log ratio of tumor sizes is more powerful than single-arm designs or those using progression-free survival to predict phase III outcomes.

Area of Science:

  • Oncology
  • Clinical Trial Design
  • Biostatistics

Background:

  • The optimal phase II clinical trial design and endpoint for evaluating growth inhibitory agents remain debated.
  • Predicting phase III outcomes from phase II trials is crucial for drug development efficiency.

Purpose of the Study:

  • To compare the predictive power of various phase II trial designs and endpoints for growth inhibitory agents.
  • To evaluate the ability of different designs to predict known phase III results in metastatic renal cancer.

Main Methods:

  • Simulated 5,000 phase II trials by resampling patients from positive (sorafenib) and negative (AE941) phase III trials in metastatic renal cancer.
  • Assessed single-arm and randomized designs using endpoints such as response rate (RR) by RECIST, mean log ratio of tumor sizes, and progression-free survival (PFS) at 90 days (PFS-90) and overall PFS.

Main Results:

  • Single-arm trials showed a 55% positive prediction rate for sorafenib and 1% for AE941 using RR by RECIST.
  • Randomized trials (20 patients/arm) demonstrated higher positive prediction rates: RR by RECIST (55% vs 7%), log ratio (88% vs 25%), PFS-90 (64% vs 15%), and overall PFS (69% vs 9%) for sorafenib vs AE941, respectively.

Conclusions:

  • The randomized phase II design with the log ratio endpoint offers superior power to predict positive phase III results (sorafenib).
  • This design also exhibits a higher false positive rate for negative phase III results (AE941) compared to single-arm designs or those using overall PFS.

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