国产盐酸拓扑替康胶囊的安全性及耐受性Ⅰ期临床研究

摘要

Objective:To evaluate the safety and tolerability of domestic topotecan hydrochloride capsule for recommending safe and reasonable doses.Methods:The dose was escalated at three levels (1.5,1.9 and 2.3 mg·m-2) for 5 consecutive days of oral administration,and 21 days were designed as one cycle.With cohorts of 3 ～6 patients per dose level,in the first cycle subjects received topotecan capsule orally; in second cycle topotecan was given intravenously (1.5 mg·m-2) in the first day and administered orally in 2 ～5 days.Blood sampled were collected at scheduled time points in the first and second days of second cycle.If dose-limiting toxicity (DLT) happened in 2 or more in the 3 ～6 subjects at a dose level,the dose climbing would stop.Results:Totally 13 patients with histologically confirmed malignancies were enrolled into 1.5 mg· m-2 group (n =6) and 1.9 mg· m-2 group (n =7),and the maximum tolerated dose was reached if the patients completed the test.In 1.5 mg·m-2 dose group,no DLT appeared.In 1.9 mg· m-2 dose group,5 DLTs appeared,which resulted from bone marrow suppression,including grade 4 thrombocytopenia,leukopenia and reduced hemoglobin.Non-hematological toxicities were grade 1 ～2 nausea,vomiting,anorexia,weakness and transaminase elevation.Severe adverse events occurred in 2 patients of 1.9 mg·m-2 dose group; 1 patient was hospitalized due to severe thrombocytopenia and withdrawed from the trial,and 1 patient was off the study because tumor progression and then he died one week later.In 11 patients to evaluate the efficacy,1 patient acquired partial remission,5 patients with stable disease,and 5 patients in progressing.The 11 patients achieved pharmacokinetic data and absolute bioavailability.Conclusion:Domestic topotecan capsule has antitumor activity.The DLT is bone marrow suppression.The maximum tolerated dose is 1.9mg·m-2,for 5 days,and 21 days a cycle.The patients show good tolerance to the 1.5 mg· m-2 dose level.For the young patients with good physique and slight previous chemoradiotherapy,the 1.9 mg· m-2 dose level deserves further study.%目的:观察国产盐酸拓扑替康胶囊的安全性和耐受性,为国人使用该药物推荐安全合理的剂量.方法:计划按3个剂量组爬坡:1.5,1.9,2.3 mg·m-2,连续5d口服,21 d为一个周期.每个剂量组3～6例,第1个周期受试者均接受拓扑替康胶囊口服,第2个周期d1给予拓扑替康静脉给药(1.5 mg·m-2),d2 ～d5仍口服给药.在第2周期d1和d2按计划时间点采集血样.如果在一个剂量组的3～6例患者中≥2例出现剂量限制性毒性(DLT),将停止剂量爬坡.结果:共入组13例肿瘤患者,完成了1.5 mg·m-2剂量组(n=6)和1.9 mg·m-2剂量组(n=7)后,即达到最大耐受剂量.1.5 mg·m-2剂量组未出现DLT.1.9mg·m-2剂量组出现5例次DLT,主要是骨髓抑制,包括4度血小板减少、白细胞减少和血红蛋白减少.非血液学毒性主要有恶心、呕吐、厌食、乏力和转氨酶升高等,程度均为1～2级.1.9 mg·m-2剂量组发生2例严重不良事件,1例因严重的血小板减少而住院治疗并出组,1例因肿瘤进展出组后死亡.11例可评价疗效者中1例获得部分缓解(PR),5例稳定(SD),5例进展(PD).11例取得了药动学及绝对生物利用度数据.结论:国产拓扑替康胶囊具有抗肿瘤活性,DLT是骨髓抑制,最大耐受剂量是1.9 mg·m-2,连用5d,21 d为1周期.该药物在采用1.5 mg·m-2剂量水平时耐受性较好.对于年轻、体质好、既往化放疗程度轻的患者,在1.9 mg·m-2剂量水平值得进一步研究.