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Flexible, rule-based dose escalation: The cohort-sequence design
Journal article   Open access   Peer reviewed

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

Shuang Li, Xian-Jin Xie and Daniel F. Heitjan
Contemporary clinical trials communications, Vol.17, pp.100541-100541
03/2020
DOI: 10.1016/j.conctc.2020.100541
PMCID: PMC7029255
PMID: 32099932
url
https://doi.org/10.1016/j.conctc.2020.100541View
Published (Version of record) Open Access

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

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