P1.11Comparison of study designs, objectives and results of Phase I trials with cytotoxic versus non-cytotoxic anticancer agents

ABSTRACT Background: Cytotoxic anticancer agents are designed to kill tumor cells by interfering with cell division mechanisms. In contrast, non-cytotoxic anticancer agents intend to inhibit cancer growth by targeting specific proteins or signaling pathways or by activating the immune system. We investigated whether these different modes of action are reflected in study designs, objectives and results of Phase I studies. Materials and methods: We conducted a PubMed search for full length English articles published in 2012 and 2013 describing completed single-agent Phase I studies in adult patients with solid tumors. Parameters were extracted, entered into a database and used to compile summarizing tables. Results: We retrieved 191 single-agent Phase I reports. Non-cytotoxic agents were investigated in almost twice as many studies compared to cytotoxic agents (127 vs 64). In the majority of studies a 3 + 3 dose escalation design was used for both cytotoxic (64%) as well as non-cytotoxic agents (50%). The percentage of studies investigating a single tumor indication was larger with non-cytotoxic agents (29% vs 11%). On average, studies investigating non-cytotoxic agents had a slightly increased sample size (39.4 vs 31.9 patients), study duration (38.2 vs 33.0 months) and enrollment time (26.8 vs 24.5 months). The main routes of administration are intravenous (IV) and oral (PO) for both cytotoxic (78% and 17%) and non-cytotoxic agents (24% and 48%). The primary objectives in both groups were mainly safety and tolerability. The main difference in secondary objectives was the increased usage of pharmacodynamic (PD) endpoints with non-cytotoxic agents (63% vs 23%). The maximum tolerated dose (MTD) was more often reached in studies with cytotoxic agents (69% vs 33%). Small but not significant differences were seen in objective response rate (4.5% vs 6.1%) and stable disease (30.0% vs 33.5%) for cytotoxic vs non-cytotoxic agents. Conclusions: There are differences in study designs, objectives and results for studies with cytotoxic compared to non-cytotoxic agents. The main difference between the two groups is the use of a single indication (11% vs 29%), the route of administration (IV vs PO), the use of PD endpoints (23% vs 63%) and the establishment of the MTD (69% vs 33%).