Adaptive randomized phase II design for biomarker threshold selection and independent evaluation

Lindsay A. Renfro, Christina M. Coughlin, Axel F Grothey, Daniel J. Sargent

Research output: Contribution to journalArticlepeer-review

12 Scopus citations


Background: Frequently a biomarker capable of defining a patient population with enhanced response to an experimental agent is not fully validated with a known threshold at the start of a phase II trial. When such candidate predictive markers are evaluated and/or validated retrospectively, over-accrual of patients less likely to benefit from the regimen may result, leading to underpowered analyses or sub-optimal patient care. Purpose: We propose an adaptive randomized phase II study design incorporating prospective biomarker threshold identification (or non-identification), possible early futility stopping, potential mid-trial accrual restriction to marker-positive subjects, and final marker and treatment evaluation in the patient population identified as most likely to benefit. Methods: An interim analysis is used to determine whether an initially unselected trial should stop early for futility, continue without a promising marker, or adapt accrual and resize (up to a pre-determined maximum) according to a promising biomarker. Final efficacy analyses are performed in the target population identified at the interim as most likely to benefit from the experimental regimen. Simulation studies demonstrate control of false-positive error rates, power, reduced average sample size, and other favorable aspects. Results: The design performs well at identifying a truly predictive biomarker at interim analysis, and subsequently restricting accrual to patients most likely to benefit from the experimental treatment. Type I and type II error rates are adequately controlled by restricting the range of marker prevalence via the candidate thresholds, and by careful consideration of the timing of interim analysis. Conclusions: In situations where identification and validation of a naturally continuous biomarker are desired within a randomized phase II trial, the design presented herein offers a potential solution.

Original languageEnglish (US)
Article number3
JournalChinese Clinical Oncology
Issue number1
StatePublished - 2014


  • Adaptive design
  • Interim futility analysis
  • Phase II trial
  • Predictive biomarker
  • Randomized clinical trial
  • Threshold identification

ASJC Scopus subject areas

  • Oncology


Dive into the research topics of 'Adaptive randomized phase II design for biomarker threshold selection and independent evaluation'. Together they form a unique fingerprint.

Cite this