Dose-finding in phase I clinical trials based on toxicity probability intervals

Clin Trials. 2007;4(3):235-44. doi: 10.1177/1740774507079442.

Abstract

Background: Most phase I clinical trials conducted at the M. D. Anderson Cancer Center use the algorithmic 3 + 3 design, despite the availability of more advanced model-based designs such as the continual reassessment method.

Purpose: Through simple statistical modeling and computing, we develop a dose-finding design that can be easily understood and implemented by non-statisticians.

Methods: We propose a beta/binomial Bayesian model and a probabilistic up-and-down rule that allow all possible dose-assignment actions to be tabulated in a spreadsheet. We have developed an Excel macro (available at http://odin.mdacc. tmc.edu/~yuanj) that generates trial monitoring tables, which contain the dose-assignment actions corresponding to various toxicity outcomes.

Results: The new design outperforms the 3 + 3 design and performs comparably to other model-based methods in the literature.

Limitations: The proposed method assumes that the observed toxicity is a binary variable and that toxicity increases with dose level.

Conclusion: The new dose-finding design enables physicians to readily determine dose assignments for new patients by referencing a trial monitoring table.

MeSH terms

  • Algorithms
  • Antineoplastic Combined Chemotherapy Protocols / administration & dosage
  • Antineoplastic Combined Chemotherapy Protocols / adverse effects
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Bayes Theorem
  • Carcinoma, Non-Small-Cell Lung / drug therapy
  • Clinical Trials, Phase I as Topic / methods*
  • Clinical Trials, Phase I as Topic / statistics & numerical data*
  • Dose-Response Relationship, Drug
  • Drug Dosage Calculations
  • Drug-Related Side Effects and Adverse Reactions*
  • Humans
  • Lung Neoplasms / drug therapy
  • Models, Statistical
  • Probability
  • Protein-Tyrosine Kinases / antagonists & inhibitors
  • Research Design

Substances

  • Protein-Tyrosine Kinases