Veltkamp Stephan A, Witteveen Els O, Capriati Angela, Crea Attilio, Animati Fabio, Voogel-Fuchs Marja, van den Heuvel Ingeborg J G M, Beijnen Jos H, Voest Emile E, Schellens Jan H M
Division of Experimental Therapy, the Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, The Netherlands.
Clin Cancer Res. 2008 Nov 15;14(22):7535-44. doi: 10.1158/1078-0432.CCR-08-0438.
To investigate i.v. administration of delimotecan (MEN 4901/T-0128), a carboxymethyldextran polymer prodrug of the active camptothecin derivative T-2513, and to assess the maximum tolerated dose, safety profile, clinical pharmacology, and antitumor activity of delimotecan and metabolites.
Patients with solid tumors refractory to standard therapy received i.v. delimotecan as 3-hour infusion once every 6 weeks. The starting dose was 150 mg/m2, followed by an accelerated dose escalation with at least one patient per dose level. The pharmacokinetics of delimotecan, T-2513, and its metabolites, SN-38, SN-38G, T-1335, T-0055, and T-3921, were assessed in plasma and urine, and their pharmacodynamics were determined by measuring the effect of the treatment on hematologic and nonhematologic toxicity.
Twenty-two patients received 35 courses. Dose-limiting toxicities were observed at 5,400 mg/m2 (n = 1), 3,600 mg/m2 (n = 1), and 2,400 mg/m2 (n = 2). The dose level of 1,800 mg/m2 was determined as maximum tolerated dose. Two partial responses were observed in patients with anal cancer (1800 mg/m2) and head and neck cancer (2400 mg/m2). Delimotecan had a long terminal half-life of 109 h, and relatively high exposures to T-2513 and SN-38 were obtained. The percentage decrease in WBC and absolute neutrophil count significantly correlated with the dose of delimotecan.
Based on its preliminary antitumor activity, safety profile, and pharmacokinetic profile, we recommend to evaluate delimotecan given as 3-hour infusion once every 6 weeks at a dose level of 1,800 mg/m2 in a phase II study.
研究静脉注射地莫替康（MEN 4901/T - 0128），一种活性喜树碱衍生物T - 2513的羧甲基葡聚糖聚合物前药，并评估地莫替康及其代谢产物的最大耐受剂量、安全性、临床药理学和抗肿瘤活性。
对标准治疗难治的实体瘤患者每6周静脉输注地莫替康3小时。起始剂量为150mg/m²，随后进行加速剂量递增，每个剂量水平至少有一名患者。在血浆和尿液中评估地莫替康、T - 2513及其代谢产物SN - 38、SN - 38G、T - 1335、T - 0055和T - 3921的药代动力学，并通过测量治疗对血液学和非血液学毒性的影响来确定其药效学。
22例患者接受了35个疗程的治疗。在5400mg/m²（n = 1）、3600mg/m²（n = 1）和2400mg/m²（n = 2）时观察到剂量限制性毒性。1800mg/m²的剂量水平被确定为最大耐受剂量。在肛管癌（1800mg/m²）和头颈癌（2400mg/m²）患者中观察到两例部分缓解。地莫替康的终末半衰期较长，为109小时，并且获得了相对较高的T - 2513和SN - 38暴露量。白细胞和绝对中性粒细胞计数的下降百分比与地莫替康的剂量显著相关。
基于其初步的抗肿瘤活性、安全性和药代动力学特征，我们建议在II期研究中评估每6周静脉输注地莫替康3小时，剂量为1800mg/m²。
