Phase I dose-finding study of BN80927 as an intravenous infusion every 21 days in patients with advanced malignant solid tumors.

Abstract

3072 Background: Homocamptothecins are novel camptothecin derivatives. The results of the first phase I trial of BN80927—a homocamptothecin inhibiting topoisomerase I and II—are reported. Methods: This open-label, multi-center, single-arm phase I study aimed to determine the maximum tolerated dose (MTD) and recommended dose (RD) of BN80927 when administered as a 30-minute intravenous (IV) infusion once every 21 days to adult patients with advanced progressive malignant solid tumors. Cohorts of ≥3 patients received a starting dose of 1.5 mg, which was increased by 25-100% with each successive cohort until the MTD (2/3, 2/6 or 3/9 patients experiencing dose-limiting toxicity [DLT]) was reached. Additional patients received repeated administrations at the RD. BN80927 was analyzed in plasma samples using a SPE-LC-MS/MS procedure. Results: BN80927 (1.5-75 mg) was administered to 56 patients (44 in the MTD determinations and 12 in the RD period). No DLTs were recorded at doses of 1.5-40 mg. The MTD was initially defined as 75 mg but after trialing 65 mg as the RD 2/6 patients had DLTs (1 with febrile neutropenia with grade 4 neutropenia; 1 with grade 4 neutropenia and grade 4 thrombocytopenia). Thus MTD was defined as 65 mg, and RD was defined as 60 mg. Twelve patients had a mean of 3.7 ± 2.35 cycles of BN80927 60 mg. Treatment Emergent Adverse Events (TEAEs) are listed in the Table. There were no BN80927-related serious adverse events at the RD. At the RD, Cmax was 1568 ± 429.5 ng·ml−1, AUC was 3172 ± 1053 ng·ml−1, and t3/4 was 15.05 ± 4.86 h. Stable disease was observed in 19/56 (33.9%) patients with mean duration of 92.9 ± 40.9 days (5/12 [41.7%] for 123.6 ± 43.4 days at RD). No patient had confirmed complete or partial response. Conclusions: The RD and MTD for BN80927 were 60 mg and 65 mg administered as a 30-minute IV infusion every 21 days. Grade ≥3 TEAEs occurring in ≥2 patients TEAE Incidence, n (%) Grade 3 Grade 4 All RD All RD Neutropenia 4 (7.1) 7 (12.5) 3 (25) Leukopenia 2 (3.6) 2 (3.6) Thrombocytopenia 3 (5.4) Febrile neutropenia 3 (5.4) Anemia 2 (3.6) Vomiting 4 (7.1) Nausea 3 (5.4) Asthenia 7 (12.5) Fatigue 4 (7.1) Gamma-glutamyltransferase increased 2 (3.6) Hemaglobin decreased 2 (3.6) Anorexia 2 (3.6) Back pain 2 (3.6) Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Ipsen Ipsen