title: A parallel phase I/II clinical trial design for combination therapies.
abstract: The use of multiple drugs in a single clinical trial or as a therapeutic strategy has become common, particularly in the treatment of cancer. Because traditional trials are designed to evaluate one agent at a time, the evaluation of therapies in combination requires specialized trial designs. In place of the traditional separate phase I and II trials, we propose using a parallel phase I/II clinical trial to evaluate simultaneously the safety and efficacy of combination dose levels, and select the optimal combination dose. The trial is started with an initial period of dose escalation, then patients are randomly assigned to admissible dose levels. These dose levels are compared with each other. Bayesian posterior probabilities are used in the randomization to adaptively assign more patients to doses with higher efficacy levels. Combination doses with lower efficacy are temporarily closed and those with intolerable toxicity are eliminated from the trial. The trial is stopped if the posterior probability for safety, efficacy, or futility crosses a prespecified boundary. For illustration, we apply the design to a combination chemotherapy trial for leukemia. We use simulation studies to assess the operating characteristics of the parallel phase I/II trial design, and compare it to a conventional design for a standard phase I and phase II trial. The simulations show that the proposed design saves sample size, has better power, and efficiently assigns more patients to doses with higher efficacy levels.
authors: Department of Biostatistics and Applied Mathematics, University of Texas, M. D. Anderson Cancer Center, Houston, Texas 77030, USA. xlhuang@mdanderson.org
authors: Xuelin
authors: X
authors: Huang
authors: Swati
authors: S
authors: Biswas
authors: Yasuhiro
authors: Y
authors: Oki
authors: Jean-Pierre
authors: JP
authors: Issa
authors: Donald A
authors: DA
authors: Berry
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects; D001499:Bayes Theorem; D001699:Biometry; D017321:Clinical Trials, Phase I as Topic / Q000706:statistics & numerical data*; D017322:Clinical Trials, Phase II as Topic / Q000706:statistics & numerical data*; D006801:Humans; D007938:Leukemia / Q000188:drug therapy; D016015:Logistic Models; D009369:Neoplasms / Q000188:drug therapy*; D016032:Randomized Controlled Trials as Topic / Q000706:statistics & numerical data; D012449:Safety