卢比替康片Ⅰ期临床耐受性研究

Phase I human tolerability trial of rubitecan tablets

目的:观察卢比替康片在人体的安全性,确定卢比替康片口服给药对肿瘤患者的最大耐受剂量(MTD)及剂量限制性毒性(DLT),为Ⅱ期临床研究提供安全有效的给药剂量及方案。另外初步观察卢比替康的抗肿瘤疗效。方法:共纳入23例晚期恶性肿瘤患者。研究分为单次给药和连续给药两部分。19例患者,分5个剂量组(0.75,1.5,2.5,3.75,5.0 mg.m-2)单次口服卢比替康片,待清除期(7 d)后,患者再接受每日1次,每周连续5 d,停2 d的连续给药方案,所对应接受的连续给药剂量为:0.5,1.0,1.3,1.5和1.8mg.m-2.d-1。其余4例患者仅进行连续给药研究,给药剂量为2.0 mg.m-2.d-1。结果:卢比替康片经口服后患者主要不良反应为消化道反应(表现为恶心、呕吐和食欲减退)、乏力、骨髓抑制,另外观察到的不良反应还包括:腹泻、发热、头晕、肝功能异常和尿常规异常。单次给药研究中,共19例患者单次服药后均未出现DLT,但因考虑到单次给药方式并非今后临床治疗的给药方式,因此未再继续进行。在连续给药第6剂量组(2.0 mg.m-2.d-1)出现DLT,MTD为1.8 mg.m-2.d-1。本研究共20例患者可评价肿瘤疗效,疗效评价:PR1例(5%),SD 8例(40%),PD 11例(55%)。结论:卢比替康用于治疗晚期恶性肿瘤患者耐受性良好,人体对卢比替康的MTD为1.8 mg.m-2.d-1。

Objective： To investigate the tolerability of rubitecan tablets in patients with advanced malignant tumors,and to determine the maximal tolerated dose（MTD） and recommend the appropriate dosage for phase II trial.Methods： In this trial,totally 23 patients with advanced malignant tumors were enrolled,and divided into two parts,namely single dose and continuous doses.Of them,19 patients were divided into 5 single dose groups（0.75,1.5,2.5,3.75 and 5.0 mg·m-2）.After taking the initial single doses,the patients received continuous doses（0.5,1.0,1.3,1.5 and 1.8 mg·m-2·d-1） for 5 days per week following 7-day washout period.The remaining 4 patients only received a continuous dose of 2.0 mg·m-2·d-1.Results： The main adverse effects included gastrointestinal reactions（nausea,vomiting and loss of appetite）,fatigue,and bone marrow suppression.Other observed adverse effects included diarrhea,fever,dizziness,liver dysfunction and abnormal urine.There was no DLT in single dose study.Considering the single dose therapy is not the way for future clinical use,it was stopped.After continuous dose of 2.0 mg·m-2·d-1,the patients experienced the DLT.The MTD in the patients was 1.8 mg·m-2·d-1.Efficacy evaluations disclosed 1 patient with PR（5%）,8 with SD（40%） and 11 with PD（55%）.Conclusion：The therapy of rubitecan is well tolerated in advanced cancer patients.The MTD is 1.8 mg·m-2·d-1.Nausea,vomiting and loss of appetite are the most frequent adverse effects.