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

Clin Cancer Res. 2012 Apr 15;18(8):2309-15. doi: 10.1158/1078-0432.CCR-11-1815. Epub 2012 Jan 27.


Purpose: The best phase II design and endpoint for growth inhibitory agents is controversial. We simulated phase II trials by resampling patients from a positive (sorafenib vs. placebo; TARGET) and a negative (AE941 vs. placebo) phase III trial in metastatic renal cancer to compare the ability of various designs and endpoints to predict the known results.

Experimental design: A total of 770 and 259 patients from TARGET and the AE 941 trial, respectively, were resampled (5,000 replicates) to simulate phase II trials with α = 0.10 (one-sided). Designs/endpoints: single arm, two-stage with response rate (RR) by Response Evaluation Criteria in Solid Tumors (RECIST; 37 patients); and randomized, two arm (20-35 patients per arm) with RR by RECIST, mean log ratio of tumor sizes (log ratio), progression-free survival (PFS) rate at 90 days (PFS-90), and overall PFS.

Results: Single-arm trials were positive with RR by RECIST in 55% and 1% of replications for sorafenib and AE 941, respectively. Randomized trials versus placebo with 20 patients per arm were positive with RR by RECIST in 55% and 7%, log ratio in 88% and 25%, PFS-90 in 64% and 15%, and overall PFS in 69% and 9% of replications for sorafenib and AE 941, respectively.

Conclusions: Compared with the single-arm design and the randomized design comparing PFS, the randomized phase II design with the log ratio endpoint has greater power to predict the positive phase III result of sorafenib in renal cancer, but a higher false positive rate for the negative phase III result of AE 941.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Benzenesulfonates / therapeutic use*
  • Clinical Trials, Phase II as Topic
  • Clinical Trials, Phase III as Topic*
  • Disease-Free Survival
  • Female
  • Humans
  • Kidney Neoplasms / drug therapy*
  • Male
  • Niacinamide / analogs & derivatives
  • Phenylurea Compounds
  • Pyridines / therapeutic use*
  • Randomized Controlled Trials as Topic*
  • Research Design*
  • Sorafenib
  • Treatment Outcome


  • Benzenesulfonates
  • Phenylurea Compounds
  • Pyridines
  • Niacinamide
  • Sorafenib