Yanaihara Tomoko, Yokoba Masanori, Onoda Sayaka, Yamamoto Michiko, Ryuge Shinichiro, Hagiri Shintaro, Katagiri Masato, Wada Mayuko, Mitsufuji Hisashi, Kubota Masaru, Arai Susumu, Kobayashi Hirosuke, Yanase Nobuo, Abe Tadashi, Masuda Noriyuki
Department of Respiratory Medicine, Kitasato University School of Medicine, 1-15-1 Kitasato Sagamihara, Kanagawa, 228-8555, Japan.
Cancer Chemother Pharmacol. 2007 Mar;59(4):419-27. doi: 10.1007/s00280-006-0279-5. Epub 2006 Jul 11.
We conducted a Phase I trial of irinotecan (CPT-11), a topoisomerase I inhibitor, combined with amrubicin, a topoisomerase II inhibitor. The aim was to determine the maximum tolerated dose (MTD) of amrubicin combined with a fixed dose of CPT-11 as well as the dose-limiting toxicities (DLT) of this combination in patients with advanced non-small cell lung cancer.
Eleven patients with stage IIIB or IV disease were treated at 3-week intervals with amrubicin (5-min intravenous injection on days 1-3) plus 60 mg/m2 of CPT-11 (90-min intravenous infusion on days 1 and 8). The starting dose of amrubicin was 25 mg/m2, and it was escalated in 5 mg/m2 increments until the maximum tolerated dose was reached.
The 30 mg/m2 of amrubicin dose was one dose level above the MTD, since three of the five patients experienced DLT during the first cycle of treatment at this dose level. Diarrhea and leukopenia were the DLT, while thrombocytopenia was only a moderate problem. Amrubicin did not affect the pharmacokinetics of CPT-11, SN-38 or SN-38 glucuronide. Except for one patient, the biliary index on day-1 correlated well with the percentage decrease of neutrophils in a sigmoid Emax model. There were five partial responses among 11 patients for an overall response rate of 45%.
The combination of amrubicin and CPT-11 seems to be active against non-small cell lung cancer with acceptable toxicity. The recommended dose for Phase II studies is 60 mg/m2 of CPT-11 (days 1 and 8) and 25 mg/m2 of amrubicin (days 1-3) administered every 21 days.
我们开展了一项伊立替康（CPT - 11，一种拓扑异构酶I抑制剂）联合氨柔比星（一种拓扑异构酶II抑制剂）的I期试验。目的是确定氨柔比星与固定剂量CPT - 11联合使用时的最大耐受剂量（MTD），以及该联合用药方案在晚期非小细胞肺癌患者中的剂量限制性毒性（DLT）。
11例III B期或IV期患者接受每3周一次的治疗，使用氨柔比星（第1 - 3天静脉注射5分钟）加60mg/m²的CPT - 11（第1天和第8天静脉输注90分钟）。氨柔比星的起始剂量为25mg/m²，以5mg/m²的增量递增，直至达到最大耐受剂量。
30mg/m²的氨柔比星剂量比MTD高一个剂量水平，因为在此剂量水平的第一个治疗周期中，5例患者中有3例出现了DLT。腹泻和白细胞减少是DLT，而血小板减少只是一个中度问题。氨柔比星不影响CPT - 11、SN - 38或SN - 38葡萄糖醛酸苷的药代动力学。除1例患者外，第1天的胆汁指数与乙状Emax模型中中性粒细胞减少百分比相关性良好。11例患者中有5例部分缓解，总缓解率为45%。
氨柔比星与CPT - 11联合使用似乎对非小细胞肺癌有效，且毒性可接受。II期研究的推荐剂量为每21天给予60mg/m²的CPT - 11（第1天和第8天）和25mg/m²的氨柔比星（第1 - 3天）。
