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Infigratinib versus gemcitabine plus cisplatin as first-line therapy in patients with advanced cholangiocarcinoma with FGFR2 gene fusions/translocations: phase 3 PROOF trial
Abou-Alfa, G. Borbath, I. Cohn, A. Goyal, L. Lamarca, Angela Macarulla, T. Oh, D. Roychowdhury, S. Sadeghi, S. Shroff, R.
Abou-Alfa, G.
Borbath, I.
Cohn, A.
Goyal, L.
Lamarca, Angela
Macarulla, T.
Oh, D.
Roychowdhury, S.
Sadeghi, S.
Shroff, R.
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Abstract
Background: Treatment options for metastatic or unresectable cholangiocarcinoma are limited with a need to provide increased disease control, improved outcomes, and targeted therapy that is less toxic than standard chemotherapy. As the understanding of the molecular landscape of cholangiocarcinoma has increased, the fibroblast growth factor receptor (FGFR) family has been found to play an important role in cholangiocarcinoma. FGFR translocations (i.e. fusion events) represent driver mutations in cholangiocarcinoma. They are present in 13e17% of intrahepatic cholangiocarcinomas (IHC) and may predict tumor sensitivity to FGFR inhibitors. Infigratinib (BGJ398) is an ATP-competitive, FGFR1e3 selective oral tyrosine kinase inhibitor that demonstrated excellent preliminary anti-tumor activity in patients with relapsed/refractory cholangiocarcinoma with FGFR2 fusions/translocations in a phase 2 study (CBJG398X2204) [Javle et al. J Clin Oncol 2018]. The PROOF trial is evaluating infigratinib versus current standard-of-care gemcitabine + cisplatin in front-line patients with advanced cholangiocarcinoma with FGFR2 gene fusions/translocations (ClinicalTrials.gov identifier: NCT03773302). Trial design: PROOF is a multicenter, open-label, randomized, controlled, phase 3 trial. Patients with previously untreated advanced/metastatic or inoperable cholangiocarcinoma with FGFR2 gene fusions (determined by local CLIA-certified or central laboratory) are randomized 2:1 to oral infigratinib 125 mg once daily for 21 days of a 28-day treatment cycle versus 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 assigned to the gemcitabine + cisplatin arm who progress can cross-over to infigratinib. The primary endpoint is progression-free survival (PFS, RECIST v1.1 by blinded 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 assessed. The trial will have sites in the US, EU, and APAC, including Australia. The target population size is 384 patients. Recruitment started in December 2019, and the study has an estimated primary completion date of September 2023.
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Date
2020
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Meetings and Proceedings
Citation
Abou-Alfa G, Borbath I, Cohn A, Goyal L, Lamarca A, Macarulla T, et al. P-144 Infigratinib versus gemcitabine plus cisplatin as first-line therapy in patients with advanced cholangiocarcinoma with FGFR2 gene fusions/translocations: phase 3 PROOF trial. Annals of Oncology. 2020;31:S136-S7.