Delayed adverse events in phase I trials of molecularly targeted and cytotoxic agents.

Background: Grade 3 and 4 adverse events (AEs) during cycle 1 are traditionally used for dose escalation decisions in Phase I oncology trials. With molecularly targeted agents (MTAs), assessment of lower grade AEs and those in later cycles is considered increasingly relevant.

Methods: We conducted a retrospective analysis of AEs in patients enrolled onto relevant phase I trials of MTAs and cytotoxic combinations (CCs) at our UK centre between 2006 and 2016. All AEs in the first six cycles deemed at least 'possibly related' were recorded.

Results: A total of 912 AEs were identified in 127 patients across 15 trials. Mean AE totals for CCs or MTAs respectively was 4.7 versus 3.0 in cycle 1, 3.8 versus 2.8 in cycles 2-6. Patients on CCs had higher mean AEs in six cycles compared to those on MTAs (8.5 vs. 5.7, p = 0.0005). For patients experiencing grade 3 AEs, 58% (CCs) and 60% (MTAs) occurred for the first time after cycle 1.

Conclusion: Overall AE incidence was lower in MTAs than CCs across six cycles. For MTAs, more frequent incidence of first grade 3/4 AEs after cycle 1 supports incorporation of delayed AEs into recommendations for Phase 2 dosing.