PROOF: A multicenter, open-label, randomized, phase III trial of infigratinib vs gemcitabine plus cisplatin in patients with advanced cholangiocarcinoma with FGFR2 gene rearrangements

Abstract

Background: Cholangiocarcinoma (CCA) treatment options are limited with a need to provide better disease control, improved outcome, and targeted therapy that is less toxic than standard chemotherapy. As the understanding of the molecular landscape of CCA has increased, the fibroblast growth factor receptor (FGFR) family has been found to play an important role in CCA. FGFR gene fusions and rearrangements represent driver mutations; they are present in 13e17% of intrahepatic CCA and may predict tumor sensitivity to FGFR inhibitors. Infigratinib (BGJ398) is an ATP-competitive, FGFR1e3 selective oral tyrosine kinase inhibitor. Based on promising preliminary response data of infigratinib in patients with relapsed/refractory CCA with FGFR2 gene fusions or other rearrangements (phase II trial CBJG398X2204), the PROOF trial is evaluating infigratinib vs gemcitabine + cisplatin in front-line patients with advanced CCA with FGFR2 gene rearrangements. Trial design: Patients with advanced/metastatic or inoperable CCA with FGFR2 gene fusions (determined by local or central laboratory) are randomized 2:1 to oral infigratinib once daily for 21 days of a 28-day treatment cycle vs intravenous standard gemcitabine (1000 mg/m2) + cisplatin (25 mg/m2) on days 1 and 8 of a 21-day cycle. Treatment will continue until confirmed progressive disease by central review, intolerance, withdrawal of informed consent, or death. Patients on the gemcitabine + cisplatin arm who develop disease progression can cross-over to receive infigratinib. The primary endpoint is progression-free survival (PFS, RECIST v1.1 central review). Secondary endpoints include overall survival, PFS (investigator determined), overall response rate, disease control rate, duration of response, and safety. Quality of life, pharmacokinetics and exploratory genetic alterations/biomarkers will also be measured. The trial will have sites in the US, EU, and APAC, including Australia. Enrollment is ongoing.