title: Design of phase I combination trials: recommendations of the Clinical Trial Design Task Force of the NCI Investigational Drug Steering Committee.
abstract: 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).
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Hospital, Baltimore;
authors.forename: Channing J
authors.initials: CJ
authors.lastname: Paller
authors.affiliation: NCIC Clinical Trials Group, Queen's University, Kingston, Ontario, Canada.
authors.forename: Penelope A
authors.initials: PA
authors.lastname: Bradbury
authors.affiliation: National Cancer Institute, Bethesda, Maryland;
authors.forename: S Percy
authors.initials: SP
authors.lastname: Ivy
authors.affiliation: NCIC Clinical Trials Group, Queen's University, Kingston, Ontario, Canada.
authors.forename: Lesley
authors.initials: L
authors.lastname: Seymour
authors.affiliation: Karmanos Cancer Institute, Detroit;
authors.forename: Patricia M
authors.initials: PM
authors.lastname: LoRusso
authors.affiliation: University of Michigan, Ann Arbor, Michigan;
authors.forename: Laurence
authors.initials: L
authors.lastname: Baker
authors.affiliation: National Cancer Institute, Bethesda, Maryland;
authors.forename: Larry
authors.initials: L
authors.lastname: Rubinstein
authors.affiliation: National Cancer Institute, Bethesda, Maryland;
authors.forename: Erich
authors.initials: E
authors.lastname: Huang
authors.affiliation: Patient Advocates in Research, Danville;
authors.forename: Deborah
authors.initials: D
authors.lastname: Collyar
authors.affiliation: Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California;
authors.forename: Susan
authors.initials: S
authors.lastname: Groshen
authors.affiliation: National Cancer Institute, Bethesda, Maryland;
authors.forename: Steven
authors.initials: S
authors.lastname: Reeves
authors.affiliation: University of Texas MD Anderson Cancer Center, Houston, Texas;
authors.forename: Lee M
authors.initials: LM
authors.lastname: Ellis
authors.affiliation: Mayo Clinic, Rochester, Minnesota;
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Sargent
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Hospital, Baltimore;
authors.forename: Gary L
authors.initials: GL
authors.lastname: Rosner
authors.affiliation: Fred Hutchinson Cancer Research Center, Cancer Research and Biostatistics, Seattle, Washington;
authors.forename: Michael L
authors.initials: ML
authors.lastname: LeBlanc
authors.affiliation: The University of Chicago, Department of Medicine, Chicago, Illinois; and mratain@medicine.bsd.uchicago.edu.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Ratain
mesh_terms: D014408:Biomarkers, Tumor / Q000032:analysis; D002985:Clinical Protocols; D017322:Clinical Trials, Phase II as Topic / Q000379:methods* / Q000592:standards*; D015507:Drugs, Investigational / Q000592:standards*; D023381:Endpoint Determination; D006801:Humans; D054547:National Cancer Institute (U.S.); D009369:Neoplasms / Q000188:drug therapy*; D018579:Patient Selection; D017410:Practice Guidelines as Topic; D012107:Research Design; D014481:United States
chemical_list: D014408:Biomarkers, Tumor; D015507:Drugs, Investigational