Phase I/II Adaptive Design for Drug Combination Oncology Trials

Stat Med. 2014 May 30;33(12):1990-2003. doi: 10.1002/sim.6097. Epub 2014 Jan 28.


Existing statistical methodology on dose finding for combination chemotherapies has focused on toxicity considerations alone in finding a maximum tolerated dose combination to recommend for further testing of efficacy in a phase II setting. Recently, there has been increasing interest in integrating phase I and phase II trials in order to facilitate drug development. In this article, we propose a new adaptive phase I/II method for dual-agent combinations that takes into account both toxicity and efficacy after each cohort inclusion. The primary objective, both within and at the conclusion of the trial, becomes finding a single dose combination with an acceptable level of toxicity that maximizes efficacious response. We assume that there exist monotone dose-toxicity and dose-efficacy relationships among doses of one agent when the dose of other agent is fixed. We perform extensive simulation studies that demonstrate the operating characteristics of our proposed approach, and we compare simulated results to existing methodology in phase I/II design for combinations of agents.

Keywords: adaptive randomization; continual reassessment method; dose finding; drug combination; phase II.

MeSH terms

  • Algorithms
  • Antineoplastic Combined Chemotherapy Protocols / administration & dosage*
  • Antineoplastic Combined Chemotherapy Protocols / adverse effects
  • Clinical Trials, Phase I as Topic*
  • Clinical Trials, Phase II as Topic*
  • Dose-Response Relationship, Drug*
  • Humans
  • Maximum Tolerated Dose*
  • Models, Statistical
  • Neoplasms / drug therapy*
  • Research Design*
  • Treatment Outcome