Phase I trial of biweekly S-1, leucovorin, oxaliplatin, and gemcitabine (the SLOG regimen) in metastatic pancreatic adenocarcinoma (mPDAC).

Abstract

369 Background: Gemcitabine and S-1 had been approved as the frontline treatment for mPDAC in Taiwan and Japan. Our previous study showed biweekly gemcitabine plus modified FOLFOX4 (the GOFL regimen) was a moderate active and well-tolerated regimen in mPDAC. To explore whether oral S-1/LV can be a substitute for infusion 5-FU/LV in combination with gemcitabine and oxaliplatin as “the SLOG regimen” to improve treatment efficacy and convenience. To define the dose-limiting toxicity (DLT), maximum tolerated dose (MTD) and preliminary anti-tumor efficacy of SLOG in patients with chemo-naïve mPDAC. Methods: Enrolled patients would receive intravenous infusion of 800 mg/m2 gemcitabine (fixed-dose rate infusion, 10 mg/m2/min) followed by 85mg/m2 oxaliplatin (2 hours) on D1 and escalating dose of oral S-1 and 20 mg/m2 leucovorin, twice daily D1-D7, every 14 days. DLTs were evaluated during the first 2 cycles of treatment. The treatment was continued until disease progression, unacceptable toxicity or withdrawal of informed consent. Results: 19 patients were enrolled into four dose levels of S-1, 20 mg/m2 (three), 30 mg/m2 (seven), 35 mg/m2 (six) and 40 mg/m2 (three). At 30 mg/m2 dose level, one patient who withdrew consent after one cycle treatment was replaced with another one. DLTs were observed in three patients, one at 30 mg/m2 (grade 3 diarrhea) and two at 40 mg/m2 (grade 3 hypersensitivity reaction and diarrhea in one each). MTD of S-1 was determined as 35 mg/m2. The median treatment duration was 8 cycles (ranged, 1-26). Of the 16 evaluable patients, the objective response rate and disease control rate were 37.5% (6 partial response, PR) and 81.3% (6 PR + 7 stable disease, SD), respectively. The median progression-free survival (PFS) was 4.6 months. At MTD dose level, there were 4 PR and 2 SD, with 6.7 months of PFS. The most common grade 3-4 adverse events included neutropenia (26.4%), diarrhea (15.8%), ALT increased (10.5%) and anemia (10.5%). Conclusions: The MTD of S-1 was 35 mg/m2 in the SLOG regimen. Extension phase II study in mPDAC is ongoing. Clinical trial information: NCT 01415713.