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

作者：Fujiwara Yutaka; Ando Yuichi; Mukohara Toru; Kiyota Naomi; Chayahara Naoko; Mitsuma Ayako; Inada Inoue Megumi; Sawaki Masataka; Ilaria Robert Jr; Turner P Kellie; Funai Jumpei; Maeda Kaijiro; Minami Hironobu^*

来源：Cancer Chemotherapy and Pharmacology, 2013, 71(4): 991-998.

DOI：10.1007/s00280-013-2092-2

• LY573636
• Tasisulam sodium
• Phase I study
• Pharmacokinetics
• Albumin-tailored dose

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. %26lt;br%26gt;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 mu g/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 mu g 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. %26lt;br%26gt;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 %). %26lt;br%26gt;Tasisulam in doses up to dose level 3 (target C (max) 360 mu g/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.

• 出版日期2013-4