Abstract 79TiP
Background
Gemcitabine + cisplatin is the current standard of care for first-line treatment of patients with locally advanced/metastatic biliary tract cancer (BTC), but survival outcomes are poor. Aberrant TGF-β signaling may be associated with BTC pathogenesis; TGF-β activity in tumors may lead to resistance to anti–PD-(L)1 therapies. Bintrafusp alfa is a first-in-class bifunctional fusion protein composed of the extracellular domain of the TGF-βRII receptor (a TGF-β “trap”) fused to a human IgG1 mAb blocking PD-L1. In murine models, the combination of bintrafusp alfa and chemotherapy resulted in improved antitumor activity over either therapy alone. Bintrafusp alfa monotherapy previously demonstrated clinical activity and manageable safety in BTC for which standard chemotherapy failed in an expansion cohort from a phase I study (NCT02699515); the objective response rate (ORR) was 20% per independent review. In this phase II/III study, the efficacy and safety of bintrafusp alfa and gemcitabine + cisplatin vs gemcitabine + cisplatin will be evaluated.
Trial design
This multicenter, phase II/III study (NCT04066491) of patients with histologically/cytologically confirmed BTC, including intrahepatic or extrahepatic cholangiocarcinoma, gallbladder cancer, or ampullary cancer, has an open-label safety run-in part and a randomized, double-blind, placebo-controlled part. Patients may not have received treatment for locally advanced/metastatic disease and must have an ECOG performance status of ≤1. Patients who have had interstitial lung disease will be excluded. In the open-label safety run-in part, ≥12patients will receive bintrafusp alfa (2400 mg Q3W) and gemcitabine + cisplatin (D1 and D8 Q3W for 8 cycles) followed by bintrafusp alfa monotherapy (2400 mg Q3W). In the randomized part, ≤500 patients will be randomized 1:1 to receive bintrafusp alfa (2400 mg) or placebo Q3W in addition to gemcitabine + cisplatin (D1 and D8 Q3W for 8 cycles). The primary endpoint of the randomized part is overall survival; key secondary endpoints include progression-free survival, ORR, and safety. Estimated enrollment is 512 patients.
Clinical trial identification
NCT04066491.
Editorial acknowledgement
Medical writing support was provided by Spencer Hughes, PhD, of ClinicalThinking, Inc, Hamilton, New Jersey, USA, and funded by Merck KGaA, Darmstadt, Germany and GlaxoSmithKline.
Legal entity responsible for the study
Merck KGaA, Darmstadt, Germany.
Funding
Merck KGaA, Darmstadt, Germany and GlaxoSmithKline.
Disclosure
D-Y. 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; Advisory/Consultancy: ASLAN; Advisory/Consultancy: Halozyme; Advisory/Consultancy: Zymeworks; Advisory/Consultancy: Celgene; Research grant/Funding (self): Array; Research grant/Funding (self): Eli Lilly. F. de Braud: Advisory/Consultancy: Tiziana Life Sciences; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution), Travel/Accommodation/Expenses: BMS; Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Celgene; Advisory/Consultancy, Research grant/Funding (institution): Novartis; Advisory/Consultancy: Servier; Advisory/Consultancy: Pharm Research Associated; Advisory/Consultancy: Daiichi Sankyo; Advisory/Consultancy, Speaker Bureau/Expert testimony: Ignyta; Advisory/Consultancy, Travel/Accommodation/Expenses: Amgen; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): Pfizer; Advisory/Consultancy: Octimet Oncology; Advisory/Consultancy, Research grant/Funding (institution): Incyte; Advisory/Consultancy: Pierre Fabre; Advisory/Consultancy: Eli Lilly; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution), Travel/Accommodation/Expenses: Roche; Advisory/Consultancy: Astra Zeneca; Advisory/Consultancy: Gentili; Advisory/Consultancy, Speaker Bureau/Expert testimony: Dephaforum; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): MSD; Advisory/Consultancy, Speaker Bureau/Expert testimony: Bayer; Advisory/Consultancy: Fondazione Menarini; Speaker Bureau/Expert testimony: Biotechespert Ltd; Speaker Bureau/Expert testimony: Prime Oncology; Research grant/Funding (institution): NMS; Research grant/Funding (institution): Merck KGAA; Research grant/Funding (institution): Kymab; Research grant/Funding (institution): Tesaro. J. Bridgewater: Advisory/Consultancy: Merck-Serono; Advisory/Consultancy: Roche; Advisory/Consultancy, Speaker Bureau/Expert testimony: BMS; Advisory/Consultancy, Research grant/Funding (institution): Incyte; Travel/Accommodation/Expenses: MSD. J. Furuse: Honoraria (self): Eisai; Honoraria (self): Bayer Yakuhin; Honoraria (self), Research grant/Funding (institution): Taiho Pharmaceutical; Honoraria (self), Research grant/Funding (institution): Ono Pharmaceutical; Honoraria (self): Novartis; Honoraria (self), Research grant/Funding (institution): Yakult Honsha; Honoraria (self): Teijin Pharma; Honoraria (self): Shionogi; Honoraria (self): EA Pharma; Honoraria (self), Research grant/Funding (institution): Eli Lilly Japan; Honoraria (self), Research grant/Funding (institution): Takeda; Honoraria (self), Research grant/Funding (institution): Chugai Pharma; Honoraria (self), Research grant/Funding (institution): Mochida Pharmaceutical; Honoraria (self), Research grant/Funding (institution): Nihon Servier; Honoraria (self), Research grant/Funding (institution): Sanofi; Honoraria (self): Fujifilm Toyama Chemical; Honoraria (self): Nobel Pharma; Honoraria (self), Research grant/Funding (institution): Pfizer; Honoraria (self): Sawai Pharmaceutical; Honoraria (self), Research grant/Funding (institution): Daiichi Sankyo; Honoraria (self), Research grant/Funding (institution): Sumitomo Dainippon; Honoraria (self): Merck Serono; Honoraria (self): Nippon Kayaku; Honoraria (self), Research grant/Funding (institution): MSD; Honoraria (self): Shire; Honoraria (self), Research grant/Funding (institution): Kyowa Hakko Kirin; Research grant/Funding (institution): J-Pharma; Research grant/Funding (institution): AstraZeneca; Research grant/Funding (institution): Astellas Pharma; Research grant/Funding (institution): NanoCarrier; Research grant/Funding (institution): Bayer. C-H. Hsu: Honoraria (self), Advisory/Consultancy: Bristol-Meyers Squibb; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Ono Pharmaceutical; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Merck Sharp & Dohme; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Roche; Advisory/Consultancy: Eli Lilly; Advisory/Consultancy: Genentech; Advisory/Consultancy: Merck Serono. M. Ikeda: Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Lilly; Honoraria (self): Taiho; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Chugai; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Novartis; Honoraria (self), Research grant/Funding (institution): Yakult; Honoraria (self): Teijin; Honoraria (self), Advisory/Consultancy: Servier; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Eisai; Honoraria (self), Research grant/Funding (institution): Bayer; Advisory/Consultancy, Research grant/Funding (institution): AstraZeneca; Research grant/Funding (institution): Ono; Research grant/Funding (institution): Bristol Myers; Research grant/Funding (institution): MSD; Research grant/Funding (institution): J-Pharma; Research grant/Funding (institution): ASLAN; Research grant/Funding (institution): Takeda; Research grant/Funding (institution): Pfizer; Research grant/Funding (institution): Merck Serono; Research grant/Funding (institution): Astellas. M. Javle: Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution), Travel/Accommodation/Expenses: QED; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution), Travel/Accommodation/Expenses: Incyte; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Merck; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Taiho; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Klus; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Arqule; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Astra Zeneca; Speaker Bureau/Expert testimony: Agios. M. Moehler: Research grant/Funding (institution): MSD; Advisory/Consultancy: Falk Foundation; Advisory/Consultancy: Lilly; Advisory/Consultancy: Roche; Advisory/Consultancy, Research grant/Funding (institution): Pfizer; Research grant/Funding (institution): Amgen; Advisory/Consultancy, Research grant/Funding (institution): Bristol-Myers Squibb; Advisory/Consultancy, Research grant/Funding (institution): Merck Serono; Advisory/Consultancy: MCI Group. J.O. Park: Advisory/Consultancy: AstraZeneca; Advisory/Consultancy, Research grant/Funding (self): Servier; Advisory/Consultancy, Research grant/Funding (self): Celgene; Advisory/Consultancy: Sanofi; Advisory/Consultancy: Merck Serono; Research grant/Funding (self): MedPacto. C. Yoo: Honoraria (self), Advisory/Consultancy, Research grant/Funding (self): Servier; Honoraria (self): Merck Serono; Honoraria (self), Advisory/Consultancy, Research grant/Funding (self): Bayer; Honoraria (self), Advisory/Consultancy: Ipsen; Honoraria (self), Advisory/Consultancy: MSD; Honoraria (self): Celgene; Honoraria (self), Advisory/Consultancy, Research grant/Funding (self): AstraZeneca; Research grant/Funding (self): Ono Pharmaceuticals. C. Helwig: Shareholder/Stockholder/Stock options, Full/Part-time employment: Merck KGaA. M. Osada: Full/Part-time employment: Merck Biopharma. M. Borad: Research grant/Funding (institution): Senhwa Pharmaceuticals; Research grant/Funding (institution): Adaptimmune; Research grant/Funding (institution): Agios Pharmaceuticals; Research grant/Funding (institution): Halozyme Pharmaceuticals; Research grant/Funding (institution): Celgene Pharmaceuticals; Research grant/Funding (institution): EMD Merck Serono; Research grant/Funding (institution): Toray; Research grant/Funding (institution): Dicerna; Research grant/Funding (institution): Taiho Pharmaceuticals; Research grant/Funding (institution): Sun Biopharma; Research grant/Funding (institution): Isis Pharmaceuticals; Research grant/Funding (institution): Redhill Pharmaceuticals; Research grant/Funding (institution): Boston Biomed; Research grant/Funding (institution): Basilea; Research grant/Funding (institution): Incyte Pharmaceuticals; Research grant/Funding (institution): Mirna Pharmaceuticals; Research grant/Funding (institution): Medimmune; Research grant/Funding (institution): Bioline; Research grant/Funding (institution): Sillajen; Research grant/Funding (institution): ARIAD Pharmaceuticals; Research grant/Funding (institution): PUMA Pharmaceuticals; Research grant/Funding (institution): Novartis; Research grant/Funding (institution): QED; Research grant/Funding (institution): Pieris; Advisory/Consultancy: ADC Therapeutics; Advisory/Consultancy: Exelixis; Advisory/Consultancy: Inspyr; Advisory/Consultancy: G1 Therapeutics; Advisory/Consultancy: Immunovative Therapies; Advisory/Consultancy: OncBioMune; Advisory/Consultancy: Western Oncolytics; Advisory/Consultancy: Lynx Group; Advisory/Consultancy: Genentech; Advisory/Consultancy: Merck; Advisory/Consultancy: Huya; Travel/Accommodation/Expenses: Astra Zeneca. All other authors have declared no conflicts of interest.