Department of Medical Oncology, Cancer Hospital and Institute, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China.
Cancer Chemother Pharmacol. 2013 Nov;72(5):1043-53. doi: 10.1007/s00280-013-2282-y. Epub 2013 Sep 17.
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.
Patients received once daily oral famitinib. Doses were increased from 4 to 8, 13, 20, 27, 24, 25 and eventually 30 mg. Each cycle was defined as 28 days. The pharmacokinetic profile and various biomarkers were evaluated during the first cycle. Antitumor efficacy was evaluated every 8 weeks.
Fifty-four patients were evaluable for safety and efficacy. Dose-limiting toxicities were observed in 2 of 3 patients at 30 mg. 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 28.7-33.8 and 41.3-47.7 h, 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.
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 25 mg.
评估新型口服多靶点酪氨酸激酶抑制剂法米替尼（法米替尼 L-苹果酸盐）在晚期实体瘤患者中的安全性、耐受性、药代动力学和抗肿瘤活性。该药物可作用于血管内皮生长因子受体-2、血小板衍生生长因子受体、干细胞因子受体（c-kit）、FMS 样酪氨酸激酶-3 受体和原癌基因酪氨酸激酶受体。
患者每天接受一次口服法米替尼治疗。剂量从 4mg 逐渐增加至 8、13、20、27、24、25 及最终的 30mg。每个周期定义为 28 天。在第一个周期中评估药代动力学特征和各种生物标志物。每 8 周评估一次抗肿瘤疗效。
54 例患者可评估安全性和疗效。30mg 剂量组有 2 例患者出现剂量限制性毒性。法米替尼治疗的第一个周期中观察到的剂量限制性毒性包括高血压、手足皮肤反应和腹泻。随后治疗周期中，3 级高甘油三酯血症/高胆固醇血症和蛋白尿是显著的副作用。其他常见的副作用包括骨髓抑制、口腔黏膜炎、疲劳、疼痛、转氨酶或胆红素升高、周围感觉障碍和甲状腺功能减退，这些副作用大多为轻至中度。药代动力学研究表明，法米替尼或其主要代谢物 M3 无明显蓄积。法米替尼和 M3 的半衰期分别约为 28.7-33.8 和 41.3-47.7 小时。食物对法米替尼的药代动力学影响较小。确定了 8 例部分缓解，包括 6 例肾细胞癌、1 例胃肠道间质瘤（GIST）和 1 例肺泡软组织肉瘤。14 例患者的肿瘤缩小程度不同，病情稳定。
法米替尼总体耐受性良好。法米替尼具有广泛的抗肿瘤活性，值得在肾细胞癌、GIST、肝细胞癌和软组织肉瘤中进一步研究。未来的 II 期临床试验推荐剂量为 25mg。
