Abstract
BackgroundGrade 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.MethodsWe 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.ResultsA 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.ConclusionOverall 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.
Highlights
Adverse events (AEs) in early phase oncology trials play a key role in dose escalation [1], with dose-limiting toxicities (DLTs) being important
Overall adverse events (AE) incidence was lower in molecularly targeted agent (MTA) than combination cytotoxic (CC) across six cycles
A total of 127 patients’ records were accessed; of these, 67 patients were enrolled onto CCs and 60 patients were enrolled onto MTAs trials (Figure 1)
Summary
Adverse events (AEs) in early phase oncology trials play a key role in dose escalation [1], with dose-limiting toxicities (DLTs) being important. Cytotoxic agents generally exhibit more severe and higher grades of toxicity in earlier cycles [4], whereas molecularly targeted agents (MTAs) are often administered chronically until progression, making consideration of lower grade AEs and those in later cycles highly relevant [2, 5, 6]. This has led to investigators having to consider how to address both late and dose-limiting toxicities across drug types [7]. With molecularly targeted agents (MTAs), assessment of lower grade AEs and those in later cycles is considered increasingly relevant
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