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PROOF 301: A multicenter, open-label, randomized, phase 3 trial of infigratinib vs gemcitabine + cisplatin in patients with advanced cholangiocarcinoma with an FGFR2 gene fusion/rearrangement
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/rearrangements are present in 10–16% 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 unresectable locally advanced vs metastatic disease, geographic region, prior neoadjuvant/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 disease 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 infigratinib. The primary endpoint is progression-free survival (PFS; RECIST v1.1; confirmed by BICR). Secondary endpoints include overall survival, PFS (investigator 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 subsequent 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. Clinicaltrials.gov identifier: NCT03773302. The PROOF 301 trial is funded by QED Therapeutics and Helsinn Healthcare SA.
Clinical trial identification
NCT03773302.
Editorial acknowledgement
Miller Medical Communications.
Legal entity responsible for the study
QED Therapeutics, Inc. and Helsinn Healthcare SA.
Funding
QED Therapeutics, Inc. and Helsinn Healthcare SA.
Disclosures
G. Abou-Alfa: Advisory / Consultancy: Adicet, Alnylam, Astra Zeneca, Autem, Beigene, Berry Genomics, Celgene, Cend, CytomX, Eisai, Eli Lilly, Exelixis, Flatiron, Genentech/Roche, Genoscience, Helio, Incyte, Ipsen, Merck, Nerviano, QED, Redhill, Rafael, Servier, Silenseed, Sobi, Vector, Y; Research grant / Funding (self): Arcus, Astra Zeneca, BioNtech, BMS, Celgene, Flatiron, Genentech/Roche, Genoscience, Incyte, Polaris, Puma, QED, Silenseed, Yiviva. I. Borbath: Advisory / Consultancy: QED, Ipsen, Servier; Research grant / Funding (institution): Servier; Travel / Accommodation / Expenses: Ipsen. L. Goyal: Advisory / Consultancy: Alentis Therapeutics AG, Black Diamond, H3Biomedicine, Incyte Corp., QED Therapeutics, Servier, Sirtex Medical Ltd., Taiho Oncology; Research grant / Funding (self): AstraZeneca (DMSC); Research grant / Funding (institution): Adaptimmune, Bayer, Eisai, Merck, Macrogenics, Genentech, Novartis, Incyte, Eli Lilly, Loxo Oncology, Relay Therapeutics, QED Therapeutics Inc, Servier, Taiho Oncology, Bristol Meyers Squibb, Nucana, Alentis, Exelixis; Full / Part-time employment: Massachusetts General Brigham, Mass General Hospital Cancer Center. A. Lamarca: Advisory / Consultancy: Advisory and consultancy honoraria from EISAI, Nutricia Ipsen, QED, Roche, Servier, Boston Scientific, Albireo Pharma, AstraZeneca, Boehringer Ingelheim and GENFIT. ; Speaker Bureau / Expert testimony: Speaker honoraria from Merck, Pfizer, Ipsen, Incyte, AAA, QED, Servier, Astra Zeneca and EISAI. ; Research grant / Funding (self): Member of the Knowledge Network and NETConnect Initiatives funded by Ipsen. Roche; Travel / Accommodation / Expenses: Travel and educational support from Ipsen, Pfizer, Bayer, AAA, SirtEx, Novartis, Mylan and Delcath. T. Macarulla: Advisory / Consultancy: (SOBI) Swedish Orpahn Biovitrum AB, Ability Pharmaceuticals SL, Aptitude Health, AstraZeneca, Basilea Pharma, Baxter, BioLineRX Ltd, Celgene, Eisai, Ellipses, Genzyme, Got It Consulting SL, Hirslanden/GITZ, Imedex, Incyte, Ipsen Bioscience, Inc, Janssen, Lilly. Marketing Farmacéutico & Investigación Clínica, S.L, MDS, Medscape, Novocure, Paraxel, PPD Development, Polaris, QED Therapeutics, Roche Farma, Sanofi-Aventis, Servier, Scilink Comunicación Científica SC, Surface Oncology, TRANSWORLD EDITORS, SL and Zymeworks. S. Roychowdhury: Advisory / Consultancy: QED Therapeutics Inc., Merck, AbbVie; Research grant / Funding (institution): Incyte, Helsinn. S. Sadeghi: Honoraria (self): QED Therapeutics Inc.; Advisory / Consultancy: QED Therapeutics Inc.; Research grant / Funding (institution): QED Therapeutics Inc.; Travel / Accommodation / Expenses: QED Therapeutics Inc.. R. Shroff: Advisory / Consultancy: AstraZeneca, Clovis, Genentech, Incyte, Merck, QED Therapeutics, Servier, Boehringer Ingelheim, Taiho, Zymeworks Biopharm, CAMI; Speaker Bureau / Expert testimony: Servier; Research grant / Funding (institution): Bayer, BMS, Bristol-Myers Squibb, Exelixis Pharm., IMV Inc., LOXO, Novocure, NUCANA, Pieris, Rafael Pharm., Seagen, Taiho, QED. J. Soto: Full / Part-time employment: QED Therapeutics. G. Pedrioli: Full / Part-time employment: Helsinn Healthcare SA. L. Fumagalli: Full / Part-time employment: helsinn healthcare. C. Dambkowski: Full / Part-time employment: QED THERAPEUTICS, QED THERAPEUTICS, QED THERAPEUTICS. M. Javle: Honoraria (self): QED Therapeutics, Inc., AstraZeneca/MedImmune, EMD Serono/Merck, TransThera Biosciences; Advisory / Consultancy: QED Therapeutics, Inc., Oncosil, Incyte, Mundipharma EDO GmbH, AstraZeneca, Merck, EMD Serono, Derazantinib; Research grant / Funding (institution): Transthera, Novartis, Eli Lilly. The author has declared no conflicts of interest.
