A dose-finding study was performed to evaluate the dose-limiting toxicity (DLT), maximum tolerated dose (MTD), and recommended dose (RD) for the triplet regimen S–IROX, which consists of S–1, irinotecan, and oxaliplatin. Its safety and efficacy in patients with locally advanced or metastatic pancreatic cancer were assessed.
Patients were required to have a histologically proven, adenosquamous or adenocarcinoma and should not have received chemotherapy previously. Patients were excluded if they had UGT genetic polymorphisms of homozygous UGT1A1*6 or *28 or heterozygous UGT1A1*6 and*28. A standard 3 + 3 dose-escalation design was implemented to define the recommended phase II dose using six predefined dose levels of S–IROX. Patients orally received escalating doses of S–1 (50 mg and 60 mg twice daily) on days 1–7, an escalating dose of intravenous irinotecan (100, 120, 150, 165, and 180 mg/m2) on day 1, and a fixed dose of intravenous oxaliplatin (85 mg/m2) on day 1 every two weeks.
Eighteen patients (females, 7; males, 11) were enrolled and treated with three dose levels. Four patients had metal stents because of malignant biliary obstruction and nine patients had the heterogeneous type of UGT1A1 gene. DLT was observed in 1 of 6 patients at level 0 (S–1 50 mg twice daily, irinotecan 150 mg/m2, and oxaliplatin 85 mg/m2); in 2 of 6 patients at level 1 (S–1 60 mg twice daily, irinotecan 150 mg/m2, andoxaliplatin 85 mg/m2); and in 2 of 6 patients at level 2 (S–1 60 mg twice daily, irinotecan 165 mg/m2, and oxaliplatin 85 mg/m2). In the level 2 cohort, one remaining patient is being still under observation; hence, the MTD and RD values have not been established yet. The most common grade 3 or 4 adverse events included hyperglycemia (24%), neutropenia (18%), diarrhea (18%), decreased platelet count (12%), and nausea (12%). The tumor response rate was 57.1%; among 14 patients whose response could be evaluated, 8 had partial response and 5 had stable disease.
As the phase I trial is ongoing, the MTD and RD values have not been fully established yet. Nevertheless, S–IROX appears to have a manageable toxicity profile and high antitumor activity. In the near future, one of three doses (150, 165, or 180 mg/m2) of irinotecan will be identified as the RD.
Clinical trial identification
All authors have declared no conflicts of interest.