Flexible, rule-based dose escalation: The cohort-sequence design

Shuang Li, Xian Jin Xie, Daniel F. Heitjan

Research output: Contribution to journalArticle

Abstract

Phase I oncology trials seek to acquire preliminary information on the safety of novel treatments. In current practice, most such trials employ rule-based designs that determine whether to escalate the dose using data from the current dose only. The most popular of these, the 3 + 3, is simple and familiar but inflexible and inefficient. We propose a rule-based design that addresses these deficiencies. Our method, which we denote the cohort-sequence design, is defined by a sequence of J increasing cohort sizes n=(n1,…,nJ) and corresponding critical values b=(b1,…,bJ). The idea is to begin with a small cohort size n1 and escalate through the planned doses, increasing the cohort size when we encounter toxicities. By selection of J and a safety threshold tuning parameter θ, one can create a design that will efficiently identify a target toxicity rate, potentially including a built-in dose-expansion cohort. We compared our designs to the 3 + 3 under a range of toxicity scenarios, observing that our approach generally rapidly identifies an MTD without enrolling patients unnecessarily at low doses where both toxicity and response rates are likely to be low. We have implemented the design in the R package cohortsequence.

Original languageEnglish (US)
Article number100541
JournalContemporary Clinical Trials Communications
Volume17
DOIs
StatePublished - Mar 2020

Keywords

  • Dose-expansion cohort
  • Dose-finding design
  • Drug safety
  • Phase I clinical trial

ASJC Scopus subject areas

  • Pharmacology

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