Online Program

Two Commonly Used Study Designs in a Phase I Oncology Study: Modified Continual Reassessment Method vs. Accelerated Titration Design (303181)

Keywords: Phase I, oncology, modified continual reassessment method, accelerated titration design

First-in-human phase I oncology studies have used the following two approaches for dose escalation widely: a modified continual reassessment method (mCRM) and accelerated titration method (ATM). There was consensus on the need for making informed decision for the dose escalation. For mCRM specifically, a two-parameter Bayesian logistic regression model with escalation with overdose control principle was considered to incorporate the pre-clinical data and knowledge of a low chance of DLT at the starting dose. For ATM, the criteria to trigger the “3+3” phase was lower than standard ones, since the biologically effective dose is expected to be lower than a maximum tolerated dose (MTD). The familiarity and simplicity of implementation of ATM and the accuracy and flexibility of mCRM were discussed during the study development along with the disadvantage of each approach: under-estimation of MTD and rigidity of ATM and added operational complexity as well as up-front statistical planning and extensive simulation of mCRM. The pros and cons of each design and the concerns of both clinical and statistical perspectives during the study development will be discussed.