The primary objective of a Phase I cancer clinical trial is to determine the maximum tolerated dose of a drug. The "failure probability" was proposed and used as a constraint to help identify a suitable initial dose range. The maximum tolerated dose was then determined based on a 3 + 3 cohort-based escalation scheme. Multiple simulations were conducted, and the method was evaluated according to the required sample size and accuracy and precision of maximum tolerated dose estimate. The results indicated that the median of the initial dose range suggested using a failure probability is a suitable initial dose regardless of the dose escalation sequence used for a cancer Phase I study. This initial dose required a smaller sample size and resulted in less bias of the estimated maximum tolerated dose compared with a commonly used initial dose, that is, 10% of the lethal dose. We tested our approach using real dose and toxicity outcome data from two published Phase I studies. These results indicate that adding a failure probability constraint into the calculation of the initial dose range will improve the efficiency of Phase I cancer trials. © 2014, Food and Drug Administration, Taiwan. Published by Elsevier Taiwan LLC. All rights reserved.

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