PROOF 301: A multicenter, open-label, randomized, phase 3 trial of infigratinib vs gemcitabine plus cisplatin in patients with advanced cholangiocarcinoma with an FGFR2 gene fusion/rearrangement

Abstract

Background: First-line treatment options are limited for patients with advanced cholangiocarcinoma (CCA). Genetic alterations in the fibroblast growth factor receptor (FGFR) gene play an important role in CCA. FGFR gene fusions/rear- rangements are present in 10e16% of intrahepatic CCA and may predict tumor sensitivity to FGFR inhibitors. Infigratinib (BGJ398) is a potent, orally bioavailable, selective, ATP-competitive, small-molecule tyrosine kinase inhibitor of FGFRs that showed promising clinical activity and a manageable adverse event profile in a phase 2 study in patients with previously treated, unresectable locally advanced/ metastatic CCA with an FGFR2 gene fusion/rearrangement. The multicenter, open- label, randomized, controlled phase 3 PROOF 301 trial is evaluating infigratinib vs standard-of-care gemcitabine + cisplatin as first-line treatment for patients with advanced/metastatic or inoperable CCA with an FGFR2 gene fusion/ rearrangement. Trial design: Approximately 300 patients 18 years of age with histologically or cytologically confirmed, advanced/metastatic or inoperable CCA with an FGFR2 gene fusion/rearrangement (confirmed by central laboratory) are randomized 2:1 to oral infigratinib 125 mg once daily for the first 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. Randomization will be stratified by unre- sectable locally advanced vs metastatic disease, geographic region, prior neo- adjuvant/adjuvant treatment vs none, and receipt of up to 1 cycle of gemcitabine- based chemotherapy for unresectable locally advanced/metastatic disease prior to randomization vs none. Treatment will continue until confirmed progressive dis- ease by blinded independent central review (BICR), intolerance, withdrawal of informed consent, or death. Patients on the gemcitabine + cisplatin arm who develop disease progression (confirmed by BICR) can cross-over to receive infi- gratinib. The primary endpoint is progression-free survival (PFS; RECIST v1.1; confirmed by BICR). Secondary endpoints include overall survival, PFS (investi- gator determined), overall response rate, best overall response, disease control rate, duration of response (BICR and investigator determined), and the type, frequency, and severity of adverse events (AEs) and serious AEs. PFS after sub- sequent therapy (PFS2), quality of life, pharmacokinetics and other exploratory genetic alterations/biomarkers will also be evaluated. Trial enrollment is ongoing in the US, EU, and APAC (including Australia). The data monitoring committee last reviewed the trial in December 2021.