Phase I study of the safety, pharmacokinetics and antitumor activity of famitinib

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• 作者：Aiping Zhou (1)
  Wen Zhang (1)
  Chunxiao Chang (1)
  Xiaoyan Chen (2)
  Dafang Zhong (2)
  Qiong Qin (1)
  Donghua Lou (3)
  Haoyuan Jiang (4)
  Jinwan Wang (1)
  
• 关键词：Famitinib ; Phase I trial ; Safety ; Pharmacokinetics ; Antitumor activity
• 刊名：Cancer Chemotherapy and Pharmacology
• 出版年：2013
• 出版时间：November 2013
• 年：2013
• 卷：72
• 期：5
• 页码：1043-1053
• 全文大小：
• 作者单位：Aiping Zhou (1)
  Wen Zhang (1)
  Chunxiao Chang (1)
  Xiaoyan Chen (2)
  Dafang Zhong (2)
  Qiong Qin (1)
  Donghua Lou (3)
  Haoyuan Jiang (4)
  Jinwan Wang (1)
  
  1. Department of Medical Oncology, Cancer Hospital and Institute, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China
  2. Center for Drug Metabolism and Pharmacokinetics Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
  3. Department of Epidemiology and Biostatistics, Nanjing Medical University, Nanjing, China
  4. Department of Clinical Development, Jiangsu Hengrui Medicine Co., Ltd, Lianyungang, China
  
• ISSN：1432-0843

文摘

Purpose To evaluate the safety, tolerability, pharmacokinetics and antitumor activities of famitinib (famitinib l-malate), a novel oral multitargeting tyrosine kinase inhibitor that acts against vascular endothelial growth factor receptor-2, platelet-derived growth factor receptor, stem cell factor receptor (c-kit), FMS-like tyrosine kinase-3 receptor and protooncogene tyrosine kinase receptor in patients with advanced solid cancer. Methods Patients received once daily oral famitinib. Doses were increased from 4 to 8, 13, 20, 27, 24, 25 and eventually 30mg. Each cycle was defined as 28days. The pharmacokinetic profile and various biomarkers were evaluated during the first cycle. Antitumor efficacy was evaluated every 8weeks. Results Fifty-four patients were evaluable for safety and efficacy. Dose-limiting toxicities were observed in 2 of 3 patients at 30mg. The dose-limiting toxicities observed in the first cycle of famitinib treatment included hypertension, hand-foot skin reaction and diarrhea. Grade 3 hypertriglyceridemia/hypercholesterolemia and proteinuria were notable side effects in the subsequent treatment cycles. Other common side effects included bone marrow suppression, oral mucositis, fatigue, pain, elevated transaminase or bilirubin, peripheral sensory disturbance and hypothyroidism, most of which were mild to moderate in severity. Pharmacokinetic studies revealed no significant accumulation of famitinib or its major metabolite, M3. The half-lives of famitinib and M3 were approximately 28.73.8 and 41.37.7h, respectively. Food demonstrated a minimal effect on the pharmacokinetics of famitinib. Eight partial responses were determined, including 6 cases of renal cell carcinoma, 1 case of gastrointestinal stromal tumor (GIST) and 1 case of alveolar soft part sarcoma. Fourteen patients demonstrated stable disease with various degrees of tumor shrinkage. Conclusions Famitinib is generally well tolerated. Famitinib demonstrates a wide spectrum of antitumor activities, which warrants further study in renal cell carcinoma, GIST, hepatocellular carcinoma and soft tissue sarcoma. The recommended dose for future phase II clinical trials is 25mg.