苹果酸法米替尼Ⅰ期临床人体耐受性研究初步总结

Tolerability of famitinib malate:the preliminary results from phase I clinical trial

目的:考察苹果酸法米替尼在人体的耐受性、最大耐受剂量并初步考察其抗肿瘤活性。方法:52例经细胞病理学证实的晚期肿瘤患者接受法米替尼治疗,每日一次口服。剂量范围:4～27 mg。28 d为一周期,每2周期评价抗肿瘤疗效。结果:51例可评价不良反应。对既往无高血压史的患者,25和27 mg均为安全剂量。如以治疗后4周作为确定剂量限制性毒性(DLT)的观察时间,法米替尼的DLT为Ⅲ度高血压和Ⅳ度血小板减少;如以治疗后8周作为DLT的观察时间,法米替尼的DLT则包括Ⅲ度高血压、Ⅳ度血小板减少、Ⅲ度蛋白尿和Ⅲ度甘油三酯升高。在25 mg剂量水平,其他的常见不良反应包括骨髓抑制、手足皮肤反应、乏力、口腔黏膜炎、疼痛、食欲减退、恶心、胆固醇升高、转氨酶升高、胆红素升高、外周感觉障碍等。48例可评价疗效2,5和27 mg组共8例PR,包括肾癌6例,GIST 1例,腺泡状软组织肉瘤1例。此外,各1例肝癌、脂肪肉瘤和胸腺癌患者未达PR,但PFS分别达12,12.7和17个月。结论:法米替尼是一个高效、不良反应可控的分子靶向药物,对无高血压史的患者2,5 mg是安全有效剂量,可作为Ⅱ期临床研究的推荐剂量。

Objective ： To Ⅱ clinical trials, and to evaluate establish the safety the antitumor activit profile and recommended dose of famitinib malate for phase y of famitinib malate. Methods： Totally 52 patients with advanced solid maliganancies received famitinib malate, once a day, at the dose ranging from 4 to 27 mg. One cycle consisted of 28 days. The antitumor efficacy was evaluated every 2 cycles. Results： Fifty-one patients were evaluable for safety. For those patients without a history of hypertension, both 27 mg and 25 mg were safe. The dose limiting toxicities for these patients were grade Ⅲ hypertension, grade Ⅳ thrombocytopenia, grade Ⅲ proteinuria and grade Ⅲ hypertriglyceridemia if defined to occur during the first 8 weeks, and only included grade ≥ hypertension and grade Ⅳ thrombocytopenia if defined to occur during the first 4 weeks. At the dose of 25 mg, other common side effects included hematological toxicity, hand-foot skin reaction, fatigue, oral mucositis, pain, anorexia, nausea, elevation of transaminase, hypercholesterolemia, peripheral neuropathy, hypothyroidism and edema. Forty-eight patients were evaluable for efficacy. Six patients with renal cell carcinoma, 1 with alveolar soft part sarcoma and 1 with GIST achieved PR at the dose of 25 mg and 27 rag. Additional 1 patient with hepatocellular carcinoma, 1 with liposarcoma and 1 with thymic carcinoma achieved a PFS of 12 months or more. The response rate for renal cell carcinoma was 6/11 （54.5%）. Conclusion： Famitinib malate has a broad antitumor activity with manageable toxicity. The dose of 25 mg is the recommended dose for those patients without a history of hypertension in phase Ⅱ clinical trials.