4413 - Infigratinib versus gemcitabine plus cisplatin multicenter, open-label, randomized, phase 3 study in patients with advanced cholangiocarcinoma with FGFR2 gene fusions/translocations: the PROOF trial

Background

Cholangiocarcinoma is the most common biliary tract malignancy with an estimated incidence in Europe of 0.4–1.8/100,000 patients, and approximately 5,000–10,000 new cases annually in the USA. Treatment options are limited with a need to provide increased disease control, improved outcome, and targeted therapy that is less toxic than standard chemotherapy. The fibroblast growth factor receptor (FGFR) family plays an important role in cholangiocarcinoma, with FGFR2 gene fusions detected in about 15% of patients. Infigratinib is an ATP-competitive, FGFR1–3-selective oral tyrosine kinase inhibitor. Based on preliminary evidence of infigratinib efficacy in patients with relapsed/refractory cholangiocarcinoma with FGFR2 fusions/translocations (phase 2 study CBJG398X2204), the PROOF trial is evaluating infigratinib versus gemcitabine + isplatin in front-line patients with advanced cholangiocarcinoma with FGFR2 gene fusions/translocations.

Trial design

Patients with advanced/metastatic or inoperable cholangiocarcinoma are randomized 1:1 to oral infigratinib once daily for 21 days of a 28-day treatment cycle versus intravenous gemcitabine (1000 mg/m²) plus cisplatin (25 mg/m²) on days 1&8 of a 21-day cycle. Treatment will continue until confirmed progressive disease by central review, intolerance, withdrawal of informed consent, or death. After 8 cycles of gemcitabine plus cisplatin, patients can continue treatment if the investigator considers that they are deriving continued benefit. Patients on the gemcitabine plus cisplatin arm who progress can cross-over to 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, PK and exploratory genetic alterations/biomarkers will also be measured. The study was initiated in February 2019 with planned enrollment of 350 patients with confirmed FGFR2 gene fusions/translocations.

Clinical trial identification

NCT03773302.

Editorial acknowledgement

Lee Miller; Miller Medical Communications Ltd.

Legal entity responsible for the study

QED Therapeutics.

Funding

QED Therapeutics.

Disclosure

G.K. Abou-Alfa: Advisory / Consultancy, Research grant / Funding (institution): QED Therapeutics; Advisory / Consultancy: Celsion; Advisory / Consultancy, Research grant / Funding (institution): Celgene; Advisory / Consultancy: Sanofi; Advisory / Consultancy: Sillajen; Advisory / Consultancy: Boston Scientific; Advisory / Consultancy: SERVIER; Advisory / Consultancy, Research grant / Funding (institution): Agios; Advisory / Consultancy: ASLAN Pharmaceuticals; Advisory / Consultancy, Research grant / Funding (institution): Bayer; Advisory / Consultancy: Delcath Systems; Advisory / Consultancy: Eisai; Advisory / Consultancy, Research grant / Funding (institution): Halozyme; Advisory / Consultancy: Ipsen; Advisory / Consultancy: Merck Serono; Advisory / Consultancy: Sirtex Medical; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution): Medimmune; Advisory / Consultancy: Amgen; Advisory / Consultancy: Antengene; Advisory / Consultancy: Astellas; Advisory / Consultancy: Aptus Clinical; Advisory / Consultancy: Carsgen Therapeutics; Advisory / Consultancy, Research grant / Funding (institution): CASI Pharmaceuticals; Advisory / Consultancy: Onxeo; Advisory / Consultancy, Research grant / Funding (institution): Roche; Advisory / Consultancy, Research grant / Funding (institution): BMS; Advisory / Consultancy, Research grant / Funding (institution): Exelixis; Advisory / Consultancy: Daiichi Sankyo; Advisory / Consultancy: Debiopharm Group; Advisory / Consultancy: Inovio Pharmaceuticals; Advisory / Consultancy: PCI Biotech; Advisory / Consultancy: Yakult Pharmaceutical; Advisory / Consultancy: 3DMedcare; Advisory / Consultancy: Alignmed; Advisory / Consultancy, Research grant / Funding (institution): BeiGene; Advisory / Consultancy: BridgeBio Pharma; Advisory / Consultancy: Cipla; Advisory / Consultancy: Genoscience Pharma; Advisory / Consultancy: Hengrui Pharmaceutical; Advisory / Consultancy: Jazz Pharmaceuticals; Advisory / Consultancy: Kyowa Hakko Kirin; Advisory / Consultancy: LAM Therapeutics; Advisory / Consultancy, Research grant / Funding (institution): Lilly; Advisory / Consultancy: Minapharma; Advisory / Consultancy: Novella Clinical; Advisory / Consultancy: RedHill Biopharma; Advisory / Consultancy: Tekmira; Advisory / Consultancy: twoXAR; Advisory / Consultancy: Yiviva; Research grant / Funding (institution): Genentech; Research grant / Funding (institution): Incyte; Research grant / Funding (institution): MabVax; Research grant / Funding (institution): Momenta Pharmaceuticals; Research grant / Funding (institution): OncoMed; Research grant / Funding (institution): Array BioPharma; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Acta Biologica; Research grant / Funding (institution), Travel / Accommodation / Expenses: Polaris; Research grant / Funding (institution): OncoQuest; Research grant / Funding (institution): Puma Biotechnology; Spouse / Financial dependant: Silenseed; Spouse / Financial dependant: EMD Serono; Spouse / Financial dependant: Gilead Sciences; Spouse / Financial dependant: Vicus Therapeutics; Spouse / Financial dependant: CytomX Therapeutics; Spouse / Financial dependant: BiolineRx; Spouse / Financial dependant: Janssen; Spouse / Financial dependant: Loxo; Spouse / Financial dependant: Newlink Genetics; Spouse / Financial dependant: Pfizer; Spouse / Financial dependant: Pharmacyte Biotech; Spouse / Financial dependant: Pharmacyclics; Spouse / Financial dependant: Pieris Pharmaceuticals; Spouse / Financial dependant: SOBI; Spouse / Financial dependant: Targovax. I. Borbath: Advisory / Consultancy, Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Ipsen; Research grant / Funding (institution): Celgene. S.J. Clarke: Advisory / Consultancy, Speaker Bureau / Expert testimony: Merck; Advisory / Consultancy, Speaker Bureau / Expert testimony: Ipsen; Advisory / Consultancy: Bayer; Advisory / Consultancy: AstraZeneca/MedImmune; Speaker Bureau / Expert testimony: Novartis. C. Louvet: Honoraria (self), Travel / Accommodation / Expenses: Roche; Honoraria (self), Travel / Accommodation / Expenses: MSD; Honoraria (self): Halozyme; Honoraria (self): Servier. D. Oh: Advisory / Consultancy, Research grant / Funding (self): AstraZeneca; Advisory / Consultancy, Research grant / Funding (self): Novartis; Advisory / Consultancy: Genentech/Roche; Advisory / Consultancy: Merck Serono; Advisory / Consultancy: Bayer; Advisory / Consultancy: Taiho Pharmaceutical; Advisory / Consultancy: ASLAN Pharmaceuticals; Research grant / Funding (self): Array BioPharma; Research grant / Funding (self): Lilly; Research grant / Funding (self): Green Cross. J.L. Spratlin: Honoraria (self), Advisory / Consultancy: Celgene; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Sanofi; Honoraria (self), Advisory / Consultancy: Lilly/ImClone; Advisory / Consultancy: Taiho Pharmaceutical; Advisory / Consultancy, Travel / Accommodation / Expenses: Astellas. J.W. Valle: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Ipsen; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Novartis; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Merck; Advisory / Consultancy: Delcath Systems; Advisory / Consultancy: Agios; Advisory / Consultancy: Pfizer; Advisory / Consultancy: PCI Biotech; Advisory / Consultancy: Incyte; Advisory / Consultancy: Keocyt; Advisory / Consultancy: QED Therapeutics; Advisory / Consultancy: Pieris Pharmaceuticals; Advisory / Consultancy: Genoscience Pharma; Advisory / Consultancy: Mundipharma EDO; Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Nucana; Speaker Bureau / Expert testimony: Imaging Equipment Limited; Travel / Accommodation / Expenses: Celgene. K.H. Weiss: Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy, Speaker Bureau / Expert testimony: BMS; Advisory / Consultancy: Bayer; Advisory / Consultancy, Research grant / Funding (institution): Wilson Therapeutics; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): GMPO; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Univar; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Alexion Pharmaceuticals; Advisory / Consultancy, Research grant / Funding (institution): Eisai; Advisory / Consultancy: Chiesi; Advisory / Consultancy: Vivet Therapeutics; Speaker Bureau / Expert testimony: Falk Pharma; Speaker Bureau / Expert testimony: Ipsen; Licensing / Royalties: Gilead Sciences. C. Berman: Full / Part-time employment: QED Therapeutics. M. Howland: Full / Part-time employment: QED Therapeutics. Y. Ye: Full / Part-time employment: QED Therapeutics. T. Cho: Full / Part-time employment: QED Therapeutics. S. Moran: Full / Part-time employment: QED Therapeutics. All other authors have declared no conflicts of interest.