A phase I study of gemcitabine/nab-paclitaxel/S-1 chemotherapy in patients with locally advanced or metastatic pancreatic ductal adenocarcinoma.

Abstract

e16261 Background: Systemic chemotherapy is the primary treatment in patients with locally advanced or metastatic pancreatic ductal adenocarcinomas (PDAC). More effective treatment options are highly awaited . The aim of this study was to evaluate the toxicity and feasibility of triweekly gemcitabine/nab-paclitaxel/S-1 (GAS) chemotherapy in patients with locally advanced or metastatic PDAC, determine the dose-limiting toxicity (DLT) and the maximum tolerated dose (MTD) of S-1 in this regimen, and explore the preliminary efficacy. Methods: Eligible patients with locally advanced or metastatic PDAC received GAS chemotherapy on a 21-day cycle. Fixed-dose of nab-paclitaxel (125 mg/m2) and gemcitabine (1000 mg/m2) were given intravenously on days 1 and 8. Different doses of S-1 were given orally twice daily from day 1 to day 14 within a 3+3 dose escalation design. According to patients` body surface area, the dose-escalation design was as follows: patients with a body surface area of 1.25–1.5 m2 received S-1 40 mg/d initially and the dose was increased to 60 mg or 80 mg. Patients with a body surface area of more than 1.5 m2 received S-1 60 mg/d initially and the dose was increased to 80 mg or 100 mg. The primary endpoints were to evaluate the toxicity and determine the DLT and MTD of S-1. The secondary endpoint was to evaluate efficacy. Results: A total of 21 eligible patients were included. Due to the infrequence of patients with a body surface area of 1.25–1.5 m2, only 2 patients were included in cohort of S-1 40 mg. The dose-escalation for patients in this group failed to be enrolled completely. For patients with a body surface area of more than 1.5 m2, 3 DLTs in 7 patients were detected at cohort of S-1 100 mg (grade 3 thrombocytopenia with hemorrhage, grade 3 rash, and grade 3 mucositis/stomatitis). S-1 80 mg/d (body surface area: > 1.5 m2) was considered to be the MTD in GAS chemotherapy (21-day cycle). No grade 4 adverse events (AEs) or treatment-related deaths were observed. The most common occurring hematologic AE of any grade was anemia (38.1%). The most frequent nonhematologic AEs of any grade were peripheral neuropathy (38.1%), dyspepsia (23.8%), constipation (23.8%), and alopecia (23.8%). After 2 cycles of GAS chemotherapy, the objective response rate was 36.8% and the disease control rate was 94.7%. The median progression-free survival was 5.3 (95% CI, 4.6 to 6.0) months and the median overall survival was 10.3 (95% CI, 8.1 to 12.5) months. Conclusions: GAS chemotherapy (21-day cycle) with nab-paclitaxel 125 mg/m2, gemcitabine 1000 mg/m2, and S-1 80 mg/d (body surface area: > 1.5 m2) was detected with the acceptable toxicity and significant clinical control in patients with locally advanced or metastatic PDAC. It is valuable to conduct further phase II trials. Clinical trial information: ChiCTR1900027833.