Retrospective analysis of a fatal dose-finding trial

Abstract: The commonplace description of phase 1 clinical trials in oncology as "primarily concerned with safety" is belied by their near universal adoption of dose-escalation practices which are inherently unsafe. In contrast with dose titration, cohort-wise dose escalation regards patients as exchangeable, an indefensible assumption in the face of widely appreciated inter-individual heterogeneity in pharmacokinetics and pharmacodynamics (PKPD). I have previously advanced this argument in terms of a precautionary coherence principle that brings the well-known coherence notion of Cheung (2005) into contact with modern imperatives of patient-centeredness and precision dosing. Here, however, I explore these matters in some mechanistic detail by analyzing a trial of the bispecific T cell engager AFM11, in which a fatal toxicity occurred. To this end, I develop a Bayesian dose-response model for a single ordinal toxicity. By constructing this model's priors to align with the AFM11 trial as designed and conducted, I demonstrate the incompatibility of that design with any reasonable expectation of safety. Indeed, the model readily yields prospective estimates of toxic response probabilities that suggest the fatality in this trial could have been foreseen as likely.