An adaptive phase I design for identifying a biologically optimal dose for dual agent drug combinations

Sumithra J. Mandrekar, Yue Cui, Daniel J. Sargent

Research output: Contribution to journalArticlepeer-review

49 Scopus citations


Historically, designs for dose seeking trials using chemotherapeutic drug combinations have been geared towards finding the maximum tolerated dose, with safety as the primary outcome. With target based agents whose dose-efficacy curves are unknown and dose-toxicity relationships may be minimal, alternative designs are needed. In this paper, we propose an extension to an adaptive single agent dose-finding design previously reported. A generalization of the continuation ratio model allowing separate toxicity and efficacy curves for each agent in a dual agent combination, generating a dose success surface for the combination, is proposed. A continual reassessment approach with a straightforward dose selection criterion using the accumulated data from all patients treated to that point is employed. Our simulation studies demonstrate favourable operating characteristics in terms of experimentation and recommendation rates, and the average sample size, under a variety of scenarios. The proposed approach allowing the incorporation of both the toxicity and efficacy of each agent into the identification of an optimal dosing region for combination is novel and warrants further consideration.

Original languageEnglish (US)
Pages (from-to)2317-2330
Number of pages14
JournalStatistics in Medicine
Issue number11
StatePublished - May 20 2007


  • Combination therapy
  • Continual reassessment method
  • Continuation ratio model
  • Efficacy
  • Phase I
  • Toxicity

ASJC Scopus subject areas

  • Epidemiology
  • Statistics and Probability


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