Takahara Naminatsu, Nakai Yousuke, Ishigami Hironori, Saito Kei, Sato Tatsuya, Hakuta Ryunosuke, Ishigaki Kazunaga, Saito Tomotaka, Hamada Tsuyoshi, Mizuno Suguru, Kogure Hirofumi, Yamashita Hiroharu, Isayama Hiroyuki, Seto Yasuyuki, Koike Kazuhiko
Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
Department of Endoscopy and Endoscopic Surgery, Graduate School of Medicine, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.
Invest New Drugs. 2021 Feb;39(1):175-181. doi: 10.1007/s10637-020-00982-7. Epub 2020 Aug 8.
A phase I study of intraperitoneal paclitaxel (ip PTX) combined with gemcitabine (GEM) plus nab-paclitaxel (nab-PTX) (GnP) was conducted to determine the maximum tolerated dose (MTD) and the recommended dose (RD) in pancreatic cancer patients with peritoneal metastasis in first-line setting.
Based on the 3 + 3 dose-escalation model, ip PTX, GEM and nab-PTX were administered at doses of 20 or 30 mg/m, 800 or 1000 mg/m and 100 or 125 mg/m (level 1, 2 and 3, respectively) on days 1, 8 and 15 in 4-week cycles. Dose-limiting toxicity (DLT) defined as severe adverse events was evaluated during the first cycle of the treatment. Safety and preliminary efficacy were also investigated.
In total, 12 patients were enrolled. While 2 of the first 6 patients enrolled at level 1 experienced DLTs (grade 3 ip port dysfunction and grade 3 pneumonia), no DLT was observed in the next 6 patients enrolled at level 2 and 3. Therefore, we did not reach the MTD and the RD was determined to be level 3 (ip PTX of 30 mg/m, GEM of 1000 mg/m, and nab-PTX of 125 mg/m). The major grade 3/4 adverse events included neutropenia (58%), anemia (33%), and ip port dysfunction (25%). The response rate was 25% and the median PFS was 5.4 (95% confidence interval; 2.4-16.0). The cytological status in peritoneal lavage turned negative in 8 patients (67%).
Ip PTX combined with GnP was feasible and potentially effective in pancreatic cancer with peritoneal metastasis as a first-line treatment deserved further evaluations.
开展一项腹腔内注射紫杉醇（ip PTX）联合吉西他滨（GEM）加纳米白蛋白结合型紫杉醇（nab-PTX）（GnP）的I期研究，以确定一线治疗伴有腹膜转移的胰腺癌患者的最大耐受剂量（MTD）和推荐剂量（RD）。
基于3+3剂量递增模型，在第1、8和15天以20或30mg/m²、800或1000mg/m²以及100或125mg/m²的剂量（分别为1、2和3级）给予ip PTX、GEM和nab-PTX，每4周为一个周期。在治疗的第一个周期评估定义为严重不良事件的剂量限制性毒性（DLT）。还研究了安全性和初步疗效。
总共纳入12例患者。虽然在1级纳入的前6例患者中有2例出现DLT（3级ip端口功能障碍和3级肺炎），但在2级和3级纳入的接下来6例患者中未观察到DLT。因此，我们未达到MTD，RD确定为3级（ip PTX 30mg/m²、GEM 1000mg/m²和nab-PTX 125mg/m²）。主要的3/4级不良事件包括中性粒细胞减少（58%）、贫血（33%）和ip端口功能障碍（25%）。缓解率为25%，中位无进展生存期为5.4（95%置信区间；2.4 - 16.0）。8例患者（67%）的腹腔灌洗细胞学状态转为阴性。
Ip PTX联合GnP作为一线治疗在伴有腹膜转移的胰腺癌中是可行的且可能有效，值得进一步评估。
