Isotonic Design for Phase I Clinical Trials: Can We Improve Further?

Isotonic design for phase I clinical trials

Abstract

One of the most challenging tasks in clinical trials is finding the maximum tolerated dose (MTD) to be tested in the next phase. An assurance for the safety of the patients and recommendation of a suitable dose for phase II are the main objectives of a phase I trial. The MTD can be identified through various approaches. A non-parametric approach, known as the isotonic design, has been explored in our study. The design relies on the monotonicity assumption of the dose-toxicity relationship. Usually the number of patients in a trial have an impact on the adequacy of dose recommendation. This paper is a humble attempt to see the impact of cohort size and total cohorts on the isotonic design. It investigates the possibility of improving the current algorithm of the isotonic design for escalation and de-escalation. Also, the paper proposes a stopping rule to avoid any severely toxic dose as the MTD. The simulation study shows that along with total cohort, cohort size also has an appreciable effect on the MTD selection. The proposed modification of the algorithm has also been found to work satisfactorily in majority of the cases.