Phase I trial of continuous infusion 9-aminocamptothecin in patients with advanced solid tumors: 21-day infusion is an active well-tolerated regimen.
Phase I trial of continuous infusion 9-aminocamptothecin in patients with advanced solid tumors: 21-day infusion is an active well-tolerated regimen.
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晚期实体瘤患者连续输注 9-氨基喜树碱的 I 期试验：21 天输注是一种积极的耐受性良好的方案。
DOI：
10.1097/00001813-200606000-00012
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发表时间：
2006
影响因子：
2.3
通讯作者：
O'Leary,James
中科院分区：
文献类型：
--
作者：
Sewak,Sanjeev;Sorich,Joan;O'Leary,James
本研究的目的是确定 9-氨基喜树碱 (9-AC) 的最大耐受剂量 (MTD)，在二甲基乙酰胺/聚乙二醇 400 (DMA) 中配制，然后以胶体分散体 (CD) 形式长期连续输注 (CI) 7-21 天，并确定 9-AC 的稳态药代动力学。对标准治疗难治的实体瘤患者被纳入这项研究。 9-AC/DMA 的总剂量/周期最初按持续时间（7-21 天）递增，同时保持剂量率恒定在 6.2 μg/m 2/h（1.04-3.12 mg/m 2/4 周周期）。然后，剂量率从 6.2 升至 21.1 μg/m 2/h（3.12–10.6 mg/m 2/4 周周期），同时保持输注持续时间恒定在 21 天。 CD配方从14.1增加至25 μg/m 2/h（7.11–12.60 mg/m 2/4周周期），同时保持输注持续时间恒定在21天，然后从28.1增加至37.5 μg/m 2/h（9.44–12.60 mg/m 2/3周周期），同时保持输注持续时间恒定在14天。天。 62 名患者可进行毒性评估； 61 人接受过既往化疗（中位数为 3 种方案/患者）。 DMA 制剂没有遇到一致的剂量限制毒性 (DLT)，直到剂量水平为 10.60 mg/m 2/周期，此时两名患者经历了 DLT。对于 21 天的 CD 制剂，五名患者中有 3 名 DLT 的 MTD 为 12.60 mg/m 2/周期。当按 14 天的时间表给予 9-AC 时，DLT 为 9.44、11.20 和 12.60 mg/m 2/周期，两个最高剂量水平的 DLT 一致。两种制剂的所有 DLT 均为 4 级血液学毒性（中性粒细胞减少症和/或血小板减少症），而非血液学毒性相对较轻（包括胃肠道毒性和疲劳）。一名卵巢癌患者获得完全缓解，三名患者获得部分缓解 (PR)。一名患有非霍奇金淋巴瘤和原发灶不明癌症的患者获得了 PR。 9-AC 两种制剂的药代动力学研究揭示了血浆 9-AC 内酯浓度与剂量增加之间的线性关系。相同剂量水平下，9-AC/CD 的血浆 9-AC 内酯浓度中值大约是 9-AC/DMA 的两倍。两种 9-AC 制剂均以 21 天 CI 给药，在 MTD 下具有剂量限制性骨髓抑制，耐受性良好。该剂量强度超过其他 9-AC I/II 期方案的剂量强度。推荐的 II 期剂量 (RPTD) 为 9.42 mg/m2/4 周周期，以 21 天输注形式给药。 9-AC/CD 的 14 天方案具有同等的骨髓抑制作用，RPTD 为 9.44 mg/m 2/3 周周期，尽管两名接受过深度治疗的患者（一名接受盆腔放疗）无法耐受该剂量。在 57 名接受过大量治疗的患者中，有 6 名患者观察到客观反应，其中大多数患有卵巢癌。
This study's objectives were to determine the maximum tolerated dose (MTD) of 9-aminocamptothecin (9-AC), given as a prolonged continuous infusion (CI) for 7–21 days, when formulated in dimethylacetamide/polyethylene glycol 400 (DMA) and then later as a colloidal dispersion (CD), and to determine the steady-state pharmacokinetics of 9-AC. Patients with solid tumors refractory to standard therapy were enrolled on this study. Total dose/cycle of 9-AC/DMA was initially escalated by duration (7–21 days), while keeping the dose rate constant at 6.2 μg/m 2/h (1.04–3.12 mg/m 2/4-week cycle). Then, the dose rate was escalated from 6.2 to 21.1 μg/m 2/h (3.12–10.6 mg/m 2/4-week cycle) while keeping the infusion duration constant at 21 days. CD formulation was escalated from 14.1 to 25 μg/m 2/h (7.11–12.60 mg/m 2/4-week cycle) while keeping the infusion duration constant at 21 days and then escalated from 28.1 to 37.5 μg/m 2/h (9.44–12.60 mg/m 2/3-week cycle) while keeping the infusion duration constant at 14 days. Sixty-two patients were evaluable for toxicity; 61 received prior chemotherapy (median 3 regimens/patient). No consistent dose-limiting toxicity (DLT) was encountered with the DMA formulation until dose level 10.60 mg/m 2/cycle, when two patients experienced DLTs. With the 21-day CD formulation, the MTD was 12.60 mg/m 2/cycle with three DLTs out of five patients. When 9-AC was given on the 14-day schedule, DLT was seen at 9.44, 11.20 and 12.60 mg/m 2/cycle, with consistent DLT at the two highest dose levels. All DLTs for both formulations were grade 4 hematologic toxicities (neutropenia and/or thrombocytopenia), while non-hematologic toxicities were relatively mild (including gastrointestinal toxicities and fatigue). One patient with ovarian cancer had a complete response and three had partial responses (PRs). One patient each with non-Hodgkin's lymphoma and cancer of unknown primary had a PR. Pharmacokinetic studies of both formulations of 9-AC revealed a linear relationship between increasing plasma 9-AC lactone concentration and dose. The median plasma 9-AC lactone concentration for 9-AC/CD was approximately twice that achieved by 9-AC/DMA for the same dose level. Both 9-AC formulations, given as a 21-day CI, were well tolerated with dose-limiting myelosupression at the MTD. This dose intensity exceeds that of other 9-AC phase I/II schedules. The recommended phase II dose (RPTD) is 9.42 mg/m 2/4-week cycle, given as a 21-day infusion. The 14-day schedule of 9-AC/CD was equally myelosuppressive with the RPTD of 9.44 mg/m 2/3-week cycle, although two heavily pre-treated patients (one with pelvic radiotherapy) could not tolerate this dose. Objective responses were observed in six out of 57 heavily pre-treated patients, most of which had ovarian cancer.