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

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• 作者：Yutaka Fujiwara (1) (3)
  Yuichi Ando (2)
  Toru Mukohara (1)
  Naomi Kiyota (1)
  Naoko Chayahara (1)
  Ayako Mitsuma (2)
  Megumi Inada-Inoue (2)
  Masataka Sawaki (2)
  Robert Ilaria Jr. (4)
  P. Kellie Turner (5)
  Jumpei Funai (6)
  Kaijiro Maeda (6)
  Hironobu Minami (1)
  
• 关键词：LY573636 ; Tasisulam sodium ; Phase I study ; Pharmacokinetics ; Albumin ; tailored dose
• 刊名：Cancer Chemotherapy and Pharmacology
• 出版年：2013
• 出版时间：April 2013
• 年：2013
• 卷：71
• 期：4
• 页码：991-998
• 全文大小：272KB
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  6. Simon GR, Ilaria RL Jr, Sovak MA, Williams CC, Haura EB, Cleverly AL, Sykes AK, Wagner MM, de Alwis DP, Slapak CA, Miller MA, Spriggs DR (2011) A phase I study of tasisulam sodium (LY573636 sodium), a novel anticancer compound in patients with refractory solid tumors. Cancer Chemother Pharmacol 68:1233-241 CrossRef
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  10. Scagliotti GV, Ilaria R Jr, Novello S, von Pawel J, Fischer JR, Ermisch S, de Alwis DP, Andrews J, Reck M, Crino L, Eschbach C, Manegold C (2012) Tasisulam sodium (LY573636 sodium) as third-line treatment in patients with unresectable, metastatic non-small-cell lung cancer: a phase-II study. J Thorac Oncol 7:1053-057 CrossRef
  11. de Alwis D, Cleverly A, Chow K, Troconiz I, Ilaria R (2010) Tailored dosing of tasisulam sodium (LY573636 sodium) to reduce hematological toxicity and improve therapeutic index. EJC Suppl 8:92-3
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• 作者单位：Yutaka Fujiwara (1) (3)
  Yuichi Ando (2)
  Toru Mukohara (1)
  Naomi Kiyota (1)
  Naoko Chayahara (1)
  Ayako Mitsuma (2)
  Megumi Inada-Inoue (2)
  Masataka Sawaki (2)
  Robert Ilaria Jr. (4)
  P. Kellie Turner (5)
  Jumpei Funai (6)
  Kaijiro Maeda (6)
  Hironobu Minami (1)
  
  1. Division of Medical Oncology/Hematology, Department of Medicine, Graduate School of Medicine, Kobe University Hospital, 7-5-2, Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan
  3. Division of Internal Medicine and Thoracic Oncology, National Cancer Center Hospital, Tokyo, 104-0045, Japan
  2. Department of Clinical Oncology and Chemotherapy, Nagoya University Hospital, Nagoya, 466-8560, Japan
  4. Eli Lilly and Company, Indianapolis, IN, 46285, USA
  5. Eli Lilly UK, Surrey, GU20 6PH, UK
  6. Eli Lilly Japan KK, Kobe, 651-0086, Japan
  
• ISSN：1432-0843

文摘

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-,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 (50-36?%). 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.