Phase I clinical trial of namitecan (ST1968): Results with D1-3 q3wks schedule.

Abstract

e13570 Background: Namitecan (N) is a topoisomerase I inhibitor with superior antitumor activity (especially in squamous cell ca., SCC) and a more favourable safety profile than irinotecan and topotecan. Pharmacokinetic (PK) studies in repeated dosing schedule (schd) showed a lack of metabolites production and no accumulation due to short half life. In first phase I studies, N was given as 2 hours iv infusion, flat dose: the recommended doses (RD) with D1, D8 q3wks and D1 q3wks schd were 15 and 23 mg, respectively. A D1-3 q3wks schd in patients (pts) with advanced solid tumors was evaluated to increase tumor exposure. Methods: Based on available PK and safety profile, the starting dose was 7 mg iv D1-3 q3wks, corresponding to an estimated D3 AUCINF of 11,850 hr*ng/mL as PK simulation from the RD of 15 mg of D1, D8 schedule. Dose escalation followed a toxicity based 3+3 cohort design. Dose-limiting toxicities (DLTs) were: ANC G4 for >5 days; febrile neutropenia; PLT ≥ G3; liver/renal toxicity ≥ G2 not recovered by D22; non-hematologic toxicity ≥ G3 (CTCAE v.3.0); delay of cycle 2 > 2 weeks (wks). PK evaluations were performed on D1, 3, 4, 5 and 11 of cycle 1. Results: So far 16 pts (7 H&N, 4 CRC, 5 others) have been treated; at 7 mg 3/6 pts experienced DLTs (2 ANC G4 > 5 days; 1 PLT G3) and the lower dose level (5 mg) has been evaluated in 9 pts with no DLTs. Next dose level will be 6 mg. ANC ≥ G3 occurred in all pts at 7 mg (median time to nadir 15 days, with recovery in <1 wk). Other toxicities were mild to moderate asthenia, nausea and vomiting. One pt with bladder carcinoma achieved a PR lasting 10+ months (mos); SD ≥ 4 mos were reported in 4 pts (endometrium, CRC, H&N and cervix ca.). As expected from PK simulation, the mean D3 AUCINF was 10700 hr*ng/mL at 7mg dose. N was linearly and proportionally related to the administered dose, being its clearance independent from plasma concentration. Due to its long half life (40-45 hr) N accumulated in plasma by a factor of 1.6 over the 3 day dosing. Conclusions: The present study confirms the safety and PK profile of N. Promising preclinical data, manageable neutropenia and hints of antitumor activity with objective response in bladder and endometrium ca support further clinical development of the compound.