749TiP - Regorafenib in locally advanced and metastatic intrahepatic or hilar cholangiocarcinoma: a randomized double-blinded phase II trial. REACH IN

Date 29 September 2014
Event ESMO 2014
Session Poster Display session
Topics Anti-Cancer Agents & Biologic Therapy
Hepatobiliary Cancers
Presenter Anne Demols
Citation Annals of Oncology (2014) 25 (suppl_4): iv210-iv253. 10.1093/annonc/mdu334
Authors A. Demols, R. Marechal, J. van Laethem
  • Gastroenterology, Hôpital Erasme, 1070 - Anderlecht/BE

Abstract

Background

There is no standard of care for advanced cholangiocarcinoma (CCK) after failure of gemcitabine and platinum-based chemotherapy. Regorafenib is potent oral multi-kinase inhibitor binding to and inhibiting kinases involved in tumor angiogenesis (VEGFR-1, -2,-3, TIE2), oncogenesis (KIT, RET, RAF-1, BRAF, BRAFV600E) and tumor microenvironment (PGDFR, FGFR). Regorafenib has recently shown to be effective in several GI tumors. Despite that CCK are usually not hypervascular tumors, regorafenib is of interest in this type of disease because of its triplepathway of kinase inhibition: -molecular alterations (disruption of MAPK pathway, activation of RAS, BRAF mutations) have been described in CCK: interest of antiproliferative profile -CCK is characterized by a dense desmoplastic stroma in which macrophages and cancer-associated fibroblasts (CAF) : interest of antistromagenesis profile -inhibition of angiogenesis in CCK is of interest as in preclinical models, sorafenib inhibits the growth of human CCK cell lines; several phase II trials treating CCK and biliary tract tumors with sorafenib have demonstrated low response rate but a trend to improve PFS and OS.

Trial design

This is a multicenter (12 Belgian centers) double-blinded placebo-controlled randomized phase II study, aiming to include 66 patients (33 patients per arm, randomization 1:1) with locally advanced (non resectable) and metastatic histologically proven intra-hepatic or hilum (mass forming) cholangiocarcinoma, progressing after gemcitabine-CDDP (or gemcitabine-oxaliplatin) or after gemcitabine alone followed or preceded by platinum-based chemotherapy. Patients will receive regorafenib / placebo (+ BSC) 160 mg od, 3 weeks on/ one week off (one cycle= 4 weeks) until progression of the disease. Primary endpoint is PFS and hypothesis made is to improve median PFS by at least 50 % (6 weeks to 12 weeks in Regorafenib group). Secondary endpoints are overall survival at one year, response rate, translational analysis. The sample size calculation is based on the logrank test, assuming a one-sided significance level of 10%, a power of 80%, a 1:1 randomization, and an improvement in median PFS of 50%.

Disclosure

All authors have declared no conflicts of interest.