A phase I, randomized, open-label, parallel-cohort, dose-finding study of elacridar (GF120918) and oral topotecan in cancer patients
A phase I, randomized, open-label, parallel-cohort, dose-finding study of elacridar (GF120918) and oral topotecan in cancer patients
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DOI：
10.1158/1078-0432.ccr-06-2414
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发表时间：
2007-06-01
影响因子：
11.5
通讯作者：
Schellens, Jan H. M.
中科院分区：
文献类型：
--
作者：
Kuppens, Isa E. L. M.;Witteveen, Els O.;Schellens, Jan H. M.
目的：乳腺癌耐药蛋白（ABCG 2）严重限制了拓扑替康的口服生物利用度。与乳腺癌耐药蛋白介导的药物转运抑制剂依克立达联合给药可增加拓扑替康的生物利用度。本研究的目的是确定依克立达的最低有效剂量，以获得拓扑替康的最大口服生物利用度，并确定口服拓扑替康和依克立达联合给药的最佳方案。在本研究的第二部分中，建立了口服拓扑替康与依克立达联合给药的剂量限制性毒性和最大耐受剂量，每日5次，每21天给药一次。在第1部分中，20名患者随机接受100、300、500、700或1，000 mg依克立达，在第1天和第8天1 h之前或同时口服2.0 mg托泊替康，也是随机化的。第15天，所有患者均接受1.5 mg/m2静脉注射拓扑替康。在研究的第11部分中，患者每日口服拓扑替康，并在第I部分之后接受最低有效剂量的依克立达治疗。最大耐受剂量和剂量限制性毒性在三名患者的队列中确定。在第一部分的第1、8和15天以及第二部分的第1和第2周期的第1天采集血样。结果：在第一部分中观察到两种方案中所有治疗组的托泊替康的完全表观口服生物利用度（102 +/- 7%）。在托泊替康剂量递增部分，两个剂量限制性毒性被认为是在2.5毫克托泊替康剂量level.Conclusion：推荐的时间表是2.0毫克口服托泊替康加100毫克依克立达伴随管理，每天5次，每21天。
Purpose: Breast cancer resistance protein (ABCG2) substantially limits the oral bioavailability of topotecan. Coadministration with elacridar, an inhibitor of breast cancer resistance protein mediated drug transport, increases the bioavailability of topotecan. The aim of this study was to establish the lowest effective dose of elacridar to obtain maximum oral bioavailability of topotecan and to determine the optimal schedule of coadministration of oral topotecan and elacridar. In the second part of this study, dose-limiting toxicities and maximum tolerated dose of oral topotecan coadministered with elacridar, at a daily times five regimen administered every 21 days, were established.Experimental Design: In part 1, 20 patients were randomized to receive 100, 300, 500,700, or 1,000 mg of elacridar on days 1 and 8 1 h before or simultaneously with 2.0 mg oral topotecan, which was also randomized. On day 15, all patients were treated with 1.5 mg/m(2) i.v. topotecan. In part 11 of the study, patients were treated daily with oral topotecan and with the lowest effective dose of elacridar following from part I. The maximum tolerated dose and dose-limiting toxicity were determined in cohorts of three patients. Blood samples were taken on days 1, 8, and 15 of part I and on day 1 of cycles 1 and 2 of part II.Results: Complete apparent oral bioavailability of topotecan (102 +/- 7%) for all treatment arms with elacridar in both schedules was seen in part I. In the topotecan dose escalation part, two dose-limiting toxicities were seen at the 2.5 mg topotecan dose level.Conclusion: The recommended schedule is 2.0 mg oral topotecan plus 100 mg elacridar administered concomitantly daily times five every 21 days.