Phase II trial of metformin and paclitaxel for patients with gemcitabine-refractory advanced adenocarcinoma of the pancreas.

Abstract

e15196 Background: Currently, there is no standard treatment for patients whose tumors progressed after 1st line gemcitabine-based regimens for pancreatic adenocarcinoma (PAC). Many pre-clinical studies have shown that metformin alone, or combined with paclitaxel, may have antitumor activity on PAC. We tested the combination of paclitaxel and metformin for patients with gemcitabine-refractory PAC. Methods: Uncontrolled phase II trial, based on a 2–stage Simon design, of metformin and paclitaxel for patients with locally advanced or metastatic PAC, ECOG 0-2, whose disease progressed on 1st line treatment with a gemcitabine-based regimen. The primary endpoint was disease control rate at 8 weeks (no progression) as per RECIST 1.1. The first stage should enroll 23 patients; if ≥ 12 patients (50%) reached the primary outcome, the study would enroll a total of 37. Patients received paclitaxel 80 mg/m2every 28 days, and metformin 850mg PO TID continuously until progression or intolerance. Results: Twenty patients were enrolled from July 2011 to January 2014. Nineteen patients were evaluable for response: N=6 (31,6%) achieved the primary endpoint, with all presenting stable disease. Median overall survival was 133 days (17 to 697) and median progression free survival was 43 days (14 to 210). Eight patients (42,1%) presented treatment-related G3-4 toxicities, with the most common being diarrhea. Six patients (31,6%) required dose-reduction of metformin because of diarrhea and one patient had paclitaxel dose-reduced due to febrile neutropenia. Conclusions: Despite the encouraging pre-clinical evidence of antitumor activity of metformin in PAC, the primary endpoint of disease control rate was not met in our trial. Besides, the treatment combination was poorly tolerated and should probably not be studied further. Clinical trial information: NCT01971034.