注射用重组人肿瘤坏死因子α衍生物aⅠ期临床耐受性研究

Phase I clinical trial and tolerance study of intravenous recombined human tumor necrosis factor-αderivative

目的：观察国人对重组人肿瘤坏死因子衍生物 a（ recombined human tumor necrosis factorα derivative,rhTNFα Da）注射液的耐受程度，毒副反应的表现及与剂量的关系，确定人体安全耐受剂量。方法： rhTNFα Da的剂量分 6级，由初试剂量 (1× 106 IU/d)开始逐级增加，每剂量级 3～ 7例共 19例。 rhTNFα Da加入 0.9％ NaCl 100 ml中静脉点滴， 50 min内滴完。连续给药 5天，停药后再观察 2周。结果：病人的主要毒副作用为发热 (89.5％ )、寒战 (87.9％ )、头痛 (26.3％ )，部分病人有恶心、呕吐。 1例恶性黑色素瘤病人达到部分缓解，客观有效率为 12.5％。结论：发热、寒战为 rhTNFα Da的主要剂量限制性毒性。 rhTNFα Da的人体最大耐受剂量为 4× 106 IU／ d。推荐Ⅱ期临床研究剂量为 3× 106 IU／ d。初步观察发现对恶性黑色素瘤有一定的客观疗效，有效率为 12.5％。

Objective: The current study was designed to determine tolerance, toxicity, maximally tolerated dose (MTD) of recombined human tumor necrosis factor α derivative (rhTNFα Da) in patients with cancer. Methods: The starting dose was 1× 106 IU/day, escalating to 2× 106 IU/day, 3× 106 IU/day and 4× 106 IU/day gradually, in cohorts of 3－ 7 patients for 5 days. The rhTNFα Da was solved in 0.9％ NS 100 ml, and was admitted through intravenous infusion in 30 min. Patients were evaluated for response for continuous two weeks. Results: Ninteen patients were assigned to this trial. The most common adverse effects were fever (89.5％ ), chilling (87.9％ ) and headache (26.3％ ). Other toxicities observed were nausea and vomiting.Partial response was achived in one patient with malignant melanoma. Objective efficacy rate was 12.5％ . Conclusion: Fever and chilling were the dose limiting side effect of rhTNFα Da. The MTD of rhTNFα Da were 4× 106 IU/day dose for PhaseⅡ clinical trails and could be 3× 106 IU/day rhTNFα Da induced an objective efficacy in the treatment of malignant melanoma in our primary study, with effective rate of 12.5％ .