Design of phase I combination trials: Recommendations of the Clinical Trial Design Task Force of the NCI Investigational Drug Steering Committee

Channing J. Paller, Penelope A. Bradbury, S. Percy Ivy, Lesley Seymour, Patricia M. LoRusso, Laurence Baker, Larry Rubinstein, Erich Huang, Deborah Collyar, Susan Groshen, Steven Reeves, Lee M. Ellis, Daniel J. Sargent, Gary L. Rosner, Michael L. LeBlanc, Mark J. Ratain

Research output: Contribution to journalReview articlepeer-review

36 Scopus citations


Anticancer drugs are combined in an effort to treat a heterogeneous tumor or to maximize the pharmacodynamic effect. The development of combination regimens, while desirable, poses unique challenges. These include the selection of agents for combination therapy that may lead to improved efficacy while maintaining acceptable toxicity, the design of clinical trials that provide informative results for individual agents and combinations, and logistic and regulatory challenges. The phase I trial is often the initial step in the clinical evaluation of a combination regimen. In view of the importance of combination regimens and the challenges associated with developing them, the Clinical Trial Design (CTD) Task Force of the National Cancer Institute Investigational Drug Steering Committee developed a set of recommendations for the phase I development of a combination regimen. The first two recommendations focus on the scientific rationale and development plans for the combination regimen; subsequent recommendations encompass clinical design aspects. The CTD Task Force recommends that selection of the proposed regimens be based on a biologic or pharmacologic rationale supported by clinical and/or robust and validated preclinical evidence, and accompanied by a plan for subsequent development of the combination. The design of the phase I clinical trial should take into consideration the potential pharmacokinetic and pharmacodynamic interactions as well as overlapping toxicity. Depending on the specific hypothesized interaction, the primary endpoint may be dose optimization, pharmacokinetics, and/or pharmacodynamics (i.e., biomarker).

Original languageEnglish (US)
Pages (from-to)4210-4217
Number of pages8
JournalClinical Cancer Research
Issue number16
StatePublished - Aug 15 2014

ASJC Scopus subject areas

  • General Medicine


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