title: A new approach to designing phase I-II cancer trials for cytotoxic chemotherapies.
abstract: Recently, there has been much work on early phase cancer designs that incorporate both toxicity and efficacy data, called phase I-II designs because they combine elements of both phases. However, they do not explicitly address the phase II hypothesis test of H0 : p ≤ p0 , where p is the probability of efficacy at the estimated maximum tolerated dose η from phase I and p0 is the baseline efficacy rate. Standard practice for phase II remains to treat p as a fixed, unknown parameter and to use Simon's two-stage design with all patients dosed at η. We propose a phase I-II design that addresses the uncertainty in the estimate p=p(η) in H0 by using sequential generalized likelihood theory. Combining this with a phase I design that incorporates efficacy data, the phase I-II design provides a common framework that can be used all the way from the first dose of phase I through the final accept/reject decision about H0 at the end of phase II, utilizing both toxicity and efficacy data throughout. Efficient group sequential testing is used in phase II that allows for early stopping to show treatment effect or futility. The proposed phase I-II design thus removes the artificial barrier between phase I and phase II and fulfills the objectives of searching for the maximum tolerated dose and testing if the treatment has an acceptable response rate to enter into a phase III trial.
authors.affiliation: Department of Mathematics, University of Southern California, 3620 South Vermont Avenue, KAP 108, Los Angeles, CA 90089, U.S.A.
authors.forename: Jay
authors.initials: J
authors.lastname: Bartroff
authors.forename: Tze Leung
authors.initials: TL
authors.lastname: Lai
authors.forename: Balasubramanian
authors.initials: B
authors.lastname: Narasimhan
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017321:Clinical Trials, Phase I as Topic / Q000379:methods / Q000706:statistics & numerical data; D017322:Clinical Trials, Phase II as Topic / Q000379:methods / Q000706:statistics & numerical data; D003603:Cytotoxins / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D020714:Maximum Tolerated Dose; D012107:Research Design
chemical_list: D000970:Antineoplastic Agents; D003603:Cytotoxins
keywords: cancer trials; generalized likelihood ratio; group sequential; isotonic regression; maximum tolerated dose; phase I; phase II