Abstract 1690: Definition of dose-limiting toxicity in phase I cancer clinical trials of molecularly targeted agents

Introduction: There is no consensus about what constitutes a dose-limiting toxicity (DLT) in phase I cancer clinical trials. We aimed to evaluate how DLTs are defined in phase I trials of molecularly targeted agents (MTA). Methods: We retrieved all phase I trials testing monotherapy with an MTA published in English after January 1st, 2000. In each trial, all items used to define DLTs were recorded. Results: Reports of 155 phase I trials evaluating 111 different MTAs were reviewed. The median DLT assessment period was 28 days [range: 7-56]. Among the 155 trials, the most common category of hematologic toxicity was “hematologic toxicity, not otherwise specified (NOS)”. Similarly, the most common category of non-hematologic toxicity was “non-hematologic toxicity, NOS”. A total of 8 other categories of hematological items and 46 categories of non-hematologic organ-specific items were employed to define DLTs in the 155 trials reviewed. Organ-specific items were reported in 111 trials (72%). Mean number of organ-specific items per trial increased from 2.03 in the 2000-2005 timeframe to 2.79 in the 2006-2010 timeframe (p=0.02). The most frequent determinant of whether a toxicity was regarded as a DLT was severity, usually assessed using the NCI CTCAE grading system. However, for any given toxicity, there was substantial variability in the degree of severity required for a toxicity to be considered a DLT. A number of other factors were increasingly found to influence the determination of DLT. Specifications about minimum duration and degree of reversibility were incorporated into the definition of a non-hematologic DLT in 13% and 12% of trials respectively. The need to delay treatment and to reduce dose-intensity because of toxicity was incorporated in the definition of DLT in 19% and 8% of trials respectively. The definition of DLT varied with administration schedule, with (near-)continuous dosing regimen often defining DLTs at lower severities. Definition of DLT did not differ according to classes of agents, to first-in-human versus not first-in-human studies or to dose escalation method used. Twenty three percent of the organ-specific DLTs defined in the trials in which non-hematologic DLTs occurred were actually encountered, suggesting an added value of these organ-specific DLTs to the generic definition. In 28 of the 155 trials (18%), toxicities were eventually considered to be DLTs even though they were not initially defined as such. Conversely, in 13 of the 155 trials (8%), toxicities were not reported as DLTs even though they were initially defined as such. Conclusions: The definition of DLT is heterogeneous across phase I cancer clinical trials of MTA administered as monotherapy and depended on the drug administration schedule. While our results do no support the standardization of the definition of DLT, we provide recommendations aiming at reducing the heterogeneity observed in the definition of DLT. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1690. doi:10.1158/1538-7445.AM2011-1690