title: An adaptive phase I design for identifying a biologically optimal dose for dual agent drug combinations.
abstract: 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 a combination is novel and warrants further consideration.
authors.affiliation: Division of Biostatistics, Mayo Clinic, Rochester, MN 55905, USA. mandrekar.sumithra@mayo.edu
authors.forename: Sumithra J
authors.initials: SJ
authors.lastname: Mandrekar
authors.forename: Yue
authors.initials: Y
authors.lastname: Cui
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Sargent
mesh_terms: D000465:Algorithms; D000971:Antineoplastic Combined Chemotherapy Protocols; D002986:Clinical Trials as Topic / Q000706:statistics & numerical data; D004305:Dose-Response Relationship, Drug; D006801:Humans; D020714:Maximum Tolerated Dose; D014481:United States