Paz-Ares L, Kunka R, DeMaria D, Cassidy J, Alden M, Beranek P, Kaye S, Littlefield D, Reilly D, Depee S, Wissel P, Twelves C, O'Dwyer P
CRC Department of Medical Oncology, University of Glasgow, Western Infirmary Hospital, UK.
Br J Cancer. 1998 Nov;78(10):1329-36. doi: 10.1038/bjc.1998.679.
GI147211 is a novel, totally synthetic camptothecin with promising preclinical and early clinical activity. This study was designed to determine the maximum tolerated dose of Gl147211 as a 72-h infusion and to describe its pharmacokinetics and pharmacodynamics on this schedule. In a single-arm, rising-dose study in patients with advanced cancer, eight cohorts of three or more patients received 72-h infusions of Gl147211 at doses ranging from 0.25 to 2.5 mg m(-2) day(-1). Forty-four patients received a total of 124 cycles. All patients had refractory tumours and 40 had received prior chemotherapy and/or radiotherapy. Whole-blood Gl147211 lactone, total blood and total concentrations were measured during and over the 12 h following the infusion. Myelosuppression was observed at all dose levels. Neutropenia was dose limiting at 2.0 mg m(-2) day(-1) in minimally pretreated patients, while both neutropenia and thrombocytopenia were limiting at 1.5 mg m(-2) day(-1) in those more heavily pretreated. Phlebitis occurred with infusions through peripheral veins early in this study, necessitating the use of central venous access. Other toxicities included mild nausea and vomiting, fatigue, headache, central venous catheter infections and alopecia. Three partial and two minor responses lasting 8-34+ weeks were noted in patients with ovarian, colon and breast carcinomas and hepatoma. Mean steady-state concentrations of Gl147211 increased with dose over a range of 0.25-1.24 ng ml(-1). The mean terminal elimination half-life was 7.5 h, and the clearance averaged 1074 ml min(-1) m(-2) over the doses studied. The mean fractional excretion of unchanged drug in urine was 0.114. Gl147211 lactone exposure correlated with haematological toxicity. The recommended phase II doses for this regimen are 1.75 mg m(-2) day(-1) and 1.2 mg m(-2) day(-1) for minimally pretreated and heavily pretreated patients respectively. At these doses, steady-state Gl147211 concentrations within the range of those effective in vitro were achieved. Extensive phase II evaluation of this compound and further phase I trials evaluating more prolonged infusions are ongoing.
GI147211是一种全新的、完全合成的喜树碱，具有良好的临床前和早期临床活性。本研究旨在确定GI147211持续72小时静脉输注的最大耐受剂量，并描述该给药方案下的药代动力学和药效学特征。在一项针对晚期癌症患者的单臂剂量递增研究中，8个队列，每个队列3名或更多患者接受了剂量范围为0.25至2.5mg m(-2) 天(-1) 的GI147211持续72小时静脉输注。44名患者共接受了124个周期的治疗。所有患者的肿瘤均难治，40名患者曾接受过化疗和/或放疗。在输注期间及输注后12小时内测定全血GI147211内酯、总血药浓度和总浓度。在所有剂量水平均观察到骨髓抑制。在预处理最少的患者中，2.0mg m(-2) 天(-1) 时中性粒细胞减少为剂量限制性毒性，而在预处理较多的患者中，1.5mg m(-2) 天(-1) 时中性粒细胞减少和血小板减少均为剂量限制性毒性。在本研究早期，经外周静脉输注时发生了静脉炎，因此需要使用中心静脉通路。其他毒性包括轻度恶心、呕吐、疲劳、头痛、中心静脉导管感染和脱发。在卵巢癌、结肠癌、乳腺癌和肝癌患者中观察到3例部分缓解和2例轻微缓解，持续时间为8 - 34 +周。GI147211的平均稳态浓度在0.25 - 1.24 ng ml(-1)范围内随剂量增加而升高。平均终末消除半衰期为7.5小时，在所研究的剂量范围内清除率平均为1074 ml min(-1) m(-2)。尿液中未变化药物的平均分数排泄率为0.114。GI147211内酯暴露与血液学毒性相关联。该方案推荐的II期剂量，预处理最少的患者为1.75mg m(-2) 天(-1)，预处理较多的患者为1.2mg m(-2) 天(-1)。在这些剂量下，达到了体外有效浓度范围内的GI147211稳态浓度。正在对该化合物进行广泛的II期评估，并开展进一步的I期试验以评估更长时间的输注。
