A Parallel Phase I/II Clinical Trial Design for Combination Therapies

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.

[1]  Peter F Thall,et al.  Dose‐Finding with Two Agents in Phase I Oncology Trials , 2003, Biometrics.

[2]  L. J. Wei,et al.  The Randomized Play-the-Winner Rule in Medical Trials , 1978 .

[3]  R Simon,et al.  Using the tolerable-dose diagram in the design of phase I combination chemotherapy trials. , 1993, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[4]  J. Issa,et al.  Results of decitabine (5‐aza‐2′deoxycytidine) therapy in 130 patients with chronic myelogenous leukemia , 2003, Cancer.

[5]  B E Storer,et al.  Design and analysis of phase I clinical trials. , 1989, Biometrics.

[6]  Jorge Cortes,et al.  Phase 1 study of low-dose prolonged exposure schedules of the hypomethylating agent 5-aza-2'-deoxycytidine (decitabine) in hematopoietic malignancies. , 2004, Blood.

[7]  D. Berry,et al.  Adaptive assignment versus balanced randomization in clinical trials: a decision analysis. , 1995, Statistics in medicine.

[8]  R Simon,et al.  Selecting drug combinations based on total equivalent dose (dose intensity) , 1990, Journal of the National Cancer Institute.

[9]  Anastasia Ivanova,et al.  Two‐Dimensional Dose Finding in Discrete Dose Space , 2005, Biometrics.

[10]  R. Simon,et al.  Selecting combinations of chemotherapeutic drugs to maximize dose intensity. , 1991, Journal of biopharmaceutical statistics.

[11]  J O'Quigley,et al.  Continual reassessment method: a practical design for phase 1 clinical trials in cancer. , 1990, Biometrics.

[12]  R. Hoffman,et al.  2-deoxy 5-azacytidine and fetal hemoglobin induction in sickle cell anemia. , 2000, Blood.

[13]  D. Berry Bayesian clinical trials , 2006, Nature Reviews Drug Discovery.

[14]  Peter F Thall,et al.  Seamlessly Expanding a Randomized Phase II Trial to Phase III , 2002, Biometrics.

[15]  R. Pearl Biometrics , 1914, The American Naturalist.

[16]  E. Gehan,et al.  The determinatio of the number of patients required in a preliminary and a follow-up trial of a new chemotherapeutic agent. , 1961, Journal of chronic diseases.

[17]  R. Simon,et al.  Optimal two-stage designs for phase II clinical trials. , 1989, Controlled clinical trials.

[18]  M. Zelen,et al.  Play the Winner Rule and the Controlled Clinical Trial , 1969 .

[19]  Donald A. Berry,et al.  Statistical Innovations in Cancer Research , 2003 .

[20]  Shyamal D Peddada,et al.  Designs for Single‐ or Multiple‐Agent Phase I Trials , 2004, Biometrics.

[21]  D. Berry Bayesian Statistics and the Efficiency and Ethics of Clinical Trials , 2004 .