Department of Medical Oncology and Therapeutics Research, City of Hope National Medical Center, 1500 East Duarte Road, Duarte, CA, 91010, USA.
Division of Biostatistics, Department of Information Sciences, City of Hope National Medical Center, Duarte, CA, USA.
Cancer Chemother Pharmacol. 2019 Mar;83(3):589-598. doi: 10.1007/s00280-019-03767-9. Epub 2019 Jan 8.
To evaluate intraperitoneal (IP) nab-paclitaxel in patients with advanced malignancies that are primarily confined to the peritoneal cavity in a phase I trial.
Using a 3 + 3 dose escalation of IP nab-paclitaxel on days 1, 8, and 15 of a 28-day cycle, we evaluated six dose levels (35-175 mg/m/dose). Maximum tolerated dose (MTD) and pharmacokinetics (PK) of IP nab-paclitaxel were determined.
There were no dose-limiting toxicities (DLTs) in cohorts 1-3. There was a DLT in one of six patients in cohort 4 (112.5 mg/m) (grade 3 neutropenia causing treatment delay > 15 days) and a DLT in one of three patients in cohort 6 (175 mg/m) (grade 4 neutropenia and grade 3 abdominal pain). A second patient in cohort 6 experienced a serious adverse event (cycle 1, grade 4 ANC ≤ 7 days, cycle 4, grade 2 left ventricular dysfunction). This dose level was determined to be above the MTD. No DLTs were seen in seven patients treated in cohort 5 (140 mg/m). The MTD of IP nab-paclitaxel was established at 140 mg/m on days 1, 8, and 15 of a 28-day cycle. There was a PK advantage for IP nab-paclitaxel, with an IP plasma area under the concentration-time curve (AUC) ratio of 147-fold (range 50-403) and therapeutic range systemic drug levels. Eight of 27 enrolled patients had progression-free survival ≥ 6 months. One patient experienced complete response, and one patient experienced partial response. Six patients had stable disease.
Weekly IP nab-paclitaxel has a favorable toxicity profile, a significant pharmacologic advantage, and promising clinical activity.
NCT00825201.
在一项 I 期试验中，评估主要局限于腹腔的晚期恶性肿瘤患者腹腔内（IP）纳布紫杉醇的疗效。
采用 IP 纳布紫杉醇 3+3 剂量递增方案，于 28 天周期的第 1、8 和 15 天给药，我们评估了 6 个剂量水平（35-175mg/m/剂量）。确定了 IP 纳布紫杉醇的最大耐受剂量（MTD）和药代动力学（PK）。
在队列 1-3 中，没有剂量限制毒性（DLT）。在队列 4 的 6 名患者中有 1 名（112.5mg/m）出现 DLT（3 级中性粒细胞减少症导致治疗延迟>15 天），在队列 6 的 3 名患者中有 1 名（175mg/m）出现 DLT（4 级中性粒细胞减少症和 3 级腹痛）。队列 6 的第 2 名患者发生了严重不良事件（第 1 周期，4 级 ANC≤7 天，第 4 周期，2 级左心室功能障碍）。该剂量水平被确定高于 MTD。在接受 140mg/m 治疗的 7 名患者中，没有观察到 DLT。在 28 天周期的第 1、8 和 15 天，IP 纳布紫杉醇的 MTD 确定为 140mg/m。IP 纳布紫杉醇具有 PK 优势，其 IP 血浆浓度-时间曲线下面积（AUC）比值为 147 倍（范围为 50-403），且达到治疗范围的系统药物水平。27 名入组患者中有 8 名无进展生存期≥6 个月。1 名患者完全缓解，1 名患者部分缓解。6 名患者病情稳定。
每周 IP 纳布紫杉醇具有良好的毒性特征、显著的药理优势和有前景的临床活性。
NCT00825201。
