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A phase I study of tasisulam sodium using an albumin-tailored dose in Japanese patients with advanced solid tumors.

Cancer Chemother Pharmacol. 2013 Feb 1;

Authors: Fujiwara Y, Ando Y, Mukohara T, Kiyota N, Chayahara N, Mitsuma A, Inada-Inoue M, Sawaki M, Ilaria R, Kellie Turner P, Funai J, Maeda K, Minami H


PURPOSE: This phase I study was designed to determine the maximum tolerated dose (MTD) and the dose to be recommended for a future phase II study of tasisulam sodium in Japanese patients with advanced, refractory solid tumors. Safety, pharmacokinetics and preliminary anti-tumor activities were assessed. Due to high-affinity albumin binding, an albumin-tailored dose to reduce the variability in tasisulam exposure was also studied. METHODS: A dose escalation scheme of tasisulam was used over 4 dose levels. Dose levels 1-3 targeted the maximum plasma concentration (C (max)) of 300, 340, and 360 μg/mL. Dose level 4 used an albumin-tailored range of C (max)-targeted doses to achieve an albumin-corrected exposure (AUCalb) of 1,200-6,400 μg h/mL, the range chosen for global tasisulam studies. Tasisulam was administered intravenously on day 1 of each 21-day (dose levels 1 and 2) or 28-day (dose levels 3 and 4) cycle. RESULTS: The major adverse events were related to bone marrow suppression, particularly neutropenia and thrombocytopenia. Dose-limiting toxicities (DLTs) were not observed until dose level 4, where 3 out of 6 patients experienced DLT, despite a tendency toward lower AUCalb variability (CV %) in the albumin-tailored dose group (38 %) compared with the targeted C (max) groups (50-236 %). CONCLUSIONS: Tasisulam in doses up to dose level 3 (target C (max) 360 μg/mL) was well tolerated. Although albumin-tailored dosing provided less AUCalb variability, a MTD that aligns with other global tasisulam studies was not identified. A lower AUCalb range may be required for the Japan population.

PMID: 23370664 [PubMed - as supplied by publisher]