The impact of non-drug-related toxicities on the estimation of the maximum tolerated dose in phase I trials.

The rate of observed dose-limiting toxicities (DLT) determines the maximum tolerated dose (MTD) in phase I trials. There are cases in which non-drug-related toxicities or other-cause toxicities (OCT) are flagged as DLTs, or vice versa, due to attribution errors. We aim to assess the impact of such errors on the final estimate of MTD. We compared the impact of attribution errors using 2 trial designs-the "3+3" dose-escalation scheme and the continual reassessment method (CRM). Two attribution errors are considered: when a DLT is classified as an OCT (type A error) and when an OCT is misclassified as a DLT (type B error). The impact of these errors on accuracy, patient safety, sample size, and study duration was evaluated by varying the probability of occurrence of each error through simulated trials. Under no errors, CRM is on average 35% more accurate than 3+3 in finding the true MTD. This improved accuracy is maintained in the presence of errors. At a 15% type B error rate, CRM recommends a dose within 2 levels of the true MTD 68% of the time, compared with 17% of the time using the 3+3 method. A DLT must be attributed as an OCT 30% of the time to increase the accuracy of 3+3; otherwise the method recommends a wrong dose approximately 75% of the time. CRM is more robust to toxicity attribution errors compared with the 3+3 as it uses information from all treated patients, leading to a more accurate MTD estimation at the frequency of attribution errors anticipated in phase I clinical trials.