Résumé
Abstract only 427 Background: News therapeutic options are needed in aBTC systemic treatment. Regorafenib (a multi target tyrosine kinase inhibitor) showed efficacy in several digestive tumors and could be associated with conventional chemotherapy in BTC. The Phase Ib primary objective was to determine the recommended Regorafenib dose combined with mGEMOX. The randomized phase II will assess efficacy of the combination compared to mGEMOX alone. We present here the results of the analysis planned at the end of phase Ib. Methods: Three dose levels (80, 120 and 160mg) of Regorafenib combined with mGEMOX, 3 to 6 patients each, were planned, and up to 12 patients to confirm the recommended dose-level. Patients received Regorafenib from day 1 to 14, and mGEMOX on days 1 and 8 (IV Gemcitabine 900mg/m2 followed with Oxaliplatin 80mg/m2 IV). Results: From 10.2014 to 11.2016, 22 patients were included in two French centers: 6, 3 and 13 patients in levels 1, 2 and 3, respectively. 2 patients (level 3) were not evaluable for recommended dose identification or tolerance and excluded from analysis. Patients were 70% men, of median age 62.5 years (20-74), ECOG PS 0 (60%) or 1 (40%). Primary tumor was localized within (60%) or outside (30%) the liver, or in the gall-bladder (10%). Eight (30%) patients underwent surgery. The Regorafenib relative dose-intensity was 101.8 [89.3-107.1], 100 [96.4-100] and 100% [51.8-103.6] for dose levels 1, 2 and 3, respectively. Regorafenib dose modifications during treatment occurred for 0 (level 1), 0 (level 2), and 3 patients (27%) (level 3). Toxicities were (level 1, 2, 3): grade 3 diarrhea (1, 0, 0), grade 3 asthenia (0, 0, 1), grade 2 hand-foot syndrome (1, 0, 0), grade 3 hypertension (2, 1, 2), grade 3/4 neutropenia (1/0, 1/0, 0/2), grade 3 thrombopenia (1, 0, 1), grade 3 anemia (0, 0, 1). Four DLTs were reported: 1 in level 1 (grade 3 diarrhea) and 3 in level 3 (2 grade 4 neutropenia, 1 grade 3 anemia). Conclusions: Regorafenib shows acceptable toxicity combined with mGEMOX; the DLTs reported were mainly related to conventional chemotherapy. Dose level 3, 160mg/day Regorafenib will be used in ongoing phase IIR assessing efficacy of this combination. Clinical trial information: NCT02386397.