Continual reassessment method with multiple toxicity constraints.

This paper addresses the dose-finding problem in cancer trials in which we are concerned with the gradation of severe toxicities that are considered dose limiting. In order to differentiate the tolerance for different toxicity types and grades, we propose a novel extension of the continual reassessment method that explicitly accounts for multiple toxicity constraints. We apply the proposed methods to redesign a bortezomib trial in lymphoma patients and compare their performance with that of the existing methods. Based on simulations, our proposed methods achieve comparable accuracy in identifying the maximum tolerated dose but have better control of the erroneous allocation and recommendation of an overdose.

[1]  M. Elkind,et al.  Stochastic approximation with virtual observations for dose-finding on discrete levels. , 2010, Biometrika.

[2]  Anastasia Ivanova,et al.  Dose Finding for Continuous and Ordinal Outcomes with a Monotone Objective Function: A Unified Approach , 2009, Biometrics.

[3]  Ying Kuen Cheung,et al.  Sequential Implementation of Stepwise Procedures for Identifying the Maximum Tolerated Dose , 2007 .

[4]  Ying Kuen Cheung,et al.  Coherence principles in dose-finding studies , 2005 .

[5]  R. Chappell,et al.  The Continual Reassessment Method for Multiple Toxicity Grades: A Bayesian Quasi‐Likelihood Approach , 2007, Biometrics.

[6]  J. Vose,et al.  Phase I/II Trial of Bortezomib + CHOP-Rituximab in Diffuse Large B Cell (DLBCL) and Mantle Cell Lymphoma (MCL): Phase I Results. , 2005 .

[7]  J. Fleiss.  Statistical methods for rates and proportions , 1974 .

[8]  S. Goodman,et al.  Some practical improvements in the continual reassessment method for phase I studies. , 1995, Statistics in medicine.

[9]  Ying Kuen Cheung,et al.  A Simple Technique to Evaluate Model Sensitivity in the Continual Reassessment Method , 2002, Biometrics.

[10]  Yuan Ji,et al.  Dose-finding in phase I clinical trials based on toxicity probability intervals , 2007, Clinical trials.

[11]  Andrew Thomas,et al.  WinBUGS - A Bayesian modelling framework: Concepts, structure, and extensibility , 2000, Stat. Comput..

[12]  Yuan Ji,et al.  Risk‐Group‐Specific Dose Finding Based on an Average Toxicity Score , 2010, Biometrics.

[13]  J. Oldenburg,et al.  Pattern and Evolution of BCR-ABL Kinase Domain Mutations in Patients with Philadelphia-Positive Acute Lymphoblastic Leukemia (Ph+ALL) Developing Resistance to Imatinib. , 2005 .

[14]  S. Durham,et al.  A random walk rule for phase I clinical trials. , 1997, Biometrics.

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

[16]  R Simon,et al.  Accelerated titration designs for phase I clinical trials in oncology. , 1997, Journal of the National Cancer Institute.

[17]  B. Nebiyou Bekele,et al.  Dose-Finding Based on Multiple Toxicities in a Soft Tissue Sarcoma Trial , 2004 .

[18]  David Gur,et al.  Area under the Free‐Response ROC Curve (FROC) and a Related Summary Index , 2009, Biometrics.

[19]  Ying Kuen Cheung,et al.  On the Use of Nonparametric Curves in Phase I Trials with Low Toxicity Tolerance , 2002, Biometrics.

[20]  Shing M. Lee,et al.  Model calibration in the continual reassessment method , 2009, Clinical trials.