Continual Reassessment Method for Partial Ordering

• Published in: Biometrics Vol. 67; no. 4; pp. 1555 - 1563
• Main Authors: Wages, Nolan A., Conaway, Mark R., O'Quigley, John
• Format: Journal Article
• Language: English; French
• Published: Malden, USA Blackwell Publishing Inc 01.12.2011; Wiley-Blackwell; Blackwell Publishing Ltd
• Subjects: Antineoplastic Agents - therapeutic use; Antineoplastic Agents - toxicity; BIOMETRIC METHODOLOGY; Biometrics; biometry; Clinical trial; Clinical trials; Clinical Trials, Phase I as Topic - methods; combination drug therapy; Continual reassessment method; Cytotoxicity; Data Interpretation, Statistical; Dosage; Dose escalation; Dose-finding studies; Drug combination; Drug combinations; Drug-Related Side Effects and Adverse Reactions - epidemiology; Drug-Related Side Effects and Adverse Reactions - etiology; Estimation methods; experimental design; Experimentation; Humans; Maximum Tolerated Dose; Neoplasms - drug therapy; Oncology; Outcome Assessment (Health Care) - methods; Parametric models; Partial ordering; patients; Phase 1 trials; Probabilities; Risk Assessment - methods; Risk Factors; Sample size; Skeleton; Statistical analysis; Toxicity; Treatment Outcome
• ISSN: 0006-341X; 1541-0420
• DOI: 10.1111/j.1541-0420.2011.01560.x

Much of the statistical methodology underlying the experimental design of phase 1 trials in oncology is intended for studies involving a single cytotoxic agent. The goal of these studies is to estimate the maximally tolerated dose, the highest dose that can be administered with an acceptable level of toxicity. A fundamental assumption of these methods is monotonicity of the dose–toxicity curve. This is a reasonable assumption for single‐agent trials in which the administration of greater doses of the agent can be expected to produce dose‐limiting toxicities in increasing proportions of patients. When studying multiple agents, the assumption may not hold because the ordering of the toxicity probabilities could possibly be unknown for several of the available drug combinations. At the same time, some of the orderings are known and so we describe the whole situation as that of a partial ordering. In this article, we propose a new two‐dimensional dose‐finding method for multiple‐agent trials that simplifies to the continual reassessment method (CRM), introduced by O'Quigley, Pepe, and Fisher (1990, Biometrics 46, 33–48), when the ordering is fully known. This design enables us to relax the assumption of a monotonic dose–toxicity curve. We compare our approach and some simulation results to a CRM design in which the ordering is known as well as to other suggestions for partial orders.