TY - JOUR
T1 - Flexible, rule-based dose escalation
T2 - The cohort-sequence design
AU - Li, Shuang
AU - Xie, Xian Jin
AU - Heitjan, Daniel F.
N1 - Publisher Copyright:
© 2020 The Author(s)
PY - 2020/3
Y1 - 2020/3
N2 - 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.
AB - 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.
KW - Dose-expansion cohort
KW - Dose-finding design
KW - Drug safety
KW - Phase I clinical trial
UR - http://www.scopus.com/inward/record.url?scp=85079398542&partnerID=8YFLogxK
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U2 - 10.1016/j.conctc.2020.100541
DO - 10.1016/j.conctc.2020.100541
M3 - Article
C2 - 32099932
AN - SCOPUS:85079398542
SN - 2451-8654
VL - 17
JO - Contemporary Clinical Trials Communications
JF - Contemporary Clinical Trials Communications
M1 - 100541
ER -