Comparison of adverse events beyond cycle 1 between cytotoxic combination and molecularly targeted phase I trials.

Abstract

e14028 Background: Traditionally, only grade 3 and 4 adverse events (AEs) occurring during cycle 1 are used for dose escalation decisions in phase I oncology trials. With the shift in cancer drug development away from cytotoxic chemotherapy towards molecularly targeted agents (MTAs), assessment of lower grade AEs and those in later cycles is considered to be of increasing relevance. This study evaluated differences in AE incidence between trial types (combination cytotoxic vs. single MTA) and cycle number (1 vs. 2-6). In line with previous work suggesting ethnic and age related differences in toxicities, we evaluated AE incidence across a range of patient demographics. Methods: Retrospective analysis of toxicity data in patients enrolled onto phase I clinical trials at a single UK centre between 2006 and 2016. All AEs in the first six cycles of treatment deemed at least ‘possibly related’ were recorded. Results: A total of 912 AEs (664, grade 1; 194, grade 2; 54, grade 3 and 4) were identified in 127 patients across 15 different trials (420 treatment cycles). Mean AE totals for patients on cytotoxic combinations and MTAs respectively were 4.51 and 2.94 in cycle 1, 3.47 and 3.04 in cycles 2-6. Patients on cytotoxic combinations experienced a significantly higher mean number of AEs in six cycles compared to those on MTAs (7.98 vs. 5.98, p = 0.0135). Of the patients experiencing grade 3-4 AEs, 57% (cytotoxic combinations) and 75% (MTAs) occurred for the first time after cycle 1. No significant difference in incidence of AEs was found between any subgroups of patient demographic variables. Conclusions: Incidence of AEs is less in MTAs than for cytotoxic combinations across cycles 1-6. The significant incidence of first grade 3-4 AEs occurring from cycle 2 onwards supports incorporation of AE assessment beyond cycle 1 into recommendations for phase II doses in MTAs.