PROOF Trial: A Multicenter, Open-Label Randomized, Phase 3 Trial of Infigratinib versus Gemcitabine plus Cisplatin in Patients with Advanced CCA with FGFR2 Gene Rearrangements

2020 Year in Review - Cholangiocarcinoma —December 20, 2020

The ongoing PROOF trial (NCT03773302) is evaluating the efficacy and safety of infigratinib versus gemcitabine plus cisplatin as frontline therapy in patients with advanced CCA harboring FGFR2 gene rearrangements.

Infigratinib (BGJ398) is a selective fibroblast growth factor receptor 1-3 (FGFR1-3) TKI that has shown promising antitumor responses in patients with relapsed/refractory CCA bearing FGFR2 alterations. In a phase 2 study (NCT02150967), infigratinib treatment resulted in confirmed overall response rate (ORR) of 26.9% (95% confidence interval [CI], 16.8%-39.1%) and median duration of response (DOR) of 5.4 months in patients with previously treated advanced CCA harboring FGFR2 fusions.1 Based on these promising results, the randomized, multicenter, open-label, phase 3 PROOF clinical trial (NCT03773302) was initiated to evaluate the efficacy and safety of infigratinib versus gemcitabine plus cisplatin as frontline therapy in patients with advanced CCA harboring FGFR2 gene rearrangements; the study design of the PROOF trial was presented at the European Society for Medical Oncology (ESMO) Virtual Congress 2020.

Study inclusion criteria included histologically or cytologically confirmed locally advanced nonresectable or metastatic CCA, documented FGFR2 gene fusions/rearrangements (by central or local laboratory), no previous systemic therapy, and Eastern Cooperative Oncology Group (ECOG) performance status 0-1. Eligible patients will be randomized 2:1 to receive oral infigratinib once daily for 21 days of a 28-day treatment cycle versus intravenous standard gemcitabine (1000 mg/m2) plus cisplatin (25 mg/m2) on days 1 and 8 of a 21-day cycle, until disease progression, intolerance, withdrawal of informed consent, or death. The study design will permit patients on the gemcitabine plus cisplatin arm to cross over to receive infigratinib on disease progression.

The primary end point is progression-free survival (PFS) as assessed by blinded independent central review (BICR); secondary end points include overall survival, PFS (investigator assessed), ORR (BICR and investigator assessed), disease control rate (BICR and investigator assessed), DOR (BICR and investigator assessed), and safety. Exploratory end points include quality of life, pharmacokinetics, and correlative genetic alterations/biomarker assessments.

Approximately 384 eligible patients are planned for study participation. Assuming a PFS HR of 0.65 between the 2 groups, 384 patients are expected to provide an approximately 90% power to demonstrate that infigratinib improves PFS versus chemotherapy at a 2-sided significance level of 0.05. An interim analysis is planned when approximately 50% of the PFS events are observed, and primary analysis after approximately 255 PFS events occur. The trial started recruitment in December 2019, with an estimated primary completion date of September 2023.

Source: Abou-Alfa G, et al. Ann Oncol. 2020;31(3_suppl). Poster 144.


  1. Javle MM, Lowery M, Shroff RT, et al. Phase II study of BGJ398 in patients with FGFR-altered advanced cholangiocarcinoma. J Clin Oncol. 2018;36:276-282.
Last modified: March 11, 2021

Subscribe to the Journal of Oncology Navigation & Survivorship®

To sign up for our print publication or e-newsletter, please enter your contact information below.

  • First Name *
    Last Name *
    Profession or Role
    Primary Specialty or Disease State
  • Please enter your mailing address.

    Address Line 2
    Zip Code