1072TiP - Phase I/II dose escalation/expansion trial to evaluate safety and preliminary efficacy of DuoBody-EpCAM×4-1BB (BNT314/GEN1059) alone or in combination with an immune checkpoint inhibitor in patients with malignant solid tumors

Background

DuoBody-EpCAM×4-1BB (BNT314/GEN1059) is an investigational bispecific antibody designed to boost antitumor immune responses by targeting costimulatory receptor 4-1BB and the epithelial cell adhesion molecule (EpCAM). Through conditional agonistic activity, BNT314/GEN1059 enhanced T cell effector function in mice (ESMO 2023 1072P). BNT314/GEN1059 is hypothesized to direct 4-1BB agonism to T cells in the tumor microenvironment of EpCAM+ tumors, and to potentiate antitumor activity of checkpoint inhibitors.

Trial design

This first-in-human, Phase 1/2, open-label, multicenter, dose escalation/expansion trial evaluates safety, efficacy, pharmacokinetics (PK), and -dynamics (PD) of BNT314/GEN1059 in patients with metastatic or advanced malignant solid tumors. It consists of a dose escalation with BNT314/GEN1059 monotherapy and an expansion part with BNT314/GEN1059 and pembrolizumab combination therapy. Primary endpoints are safety (dose-limiting toxicities (DLT), treatment-emergent adverse events, dose reductions/discontinuation, Grade ≥ 3 abnormal safety laboratory parameters); and objective response rate per RECIST 1.1 (combination part only). An adaptive trial design enables additional cohorts, doses/schedules for dose optimization, and combination compounds during dose escalation and/or in separate expansion cohorts based on dose-and exposure-response relationships, emerging safety and PK/PD. BNT314/GEN1059 will be evaluated at multiple dose levels during dose escalation using a Bayesian logistic regression model. The expansion part will start with a safety run in (SRI) to evaluate dose levels of BNT314/GEN1059 in combination with pembrolizumab in 12–28 DLT-evaluable patients. After SRI, up to 199 patients with selected cancer types will receive combination therapy. Treatment will continue until disease progression, unacceptable toxicity, or consent withdrawal, with a maximum duration of 2 years. The trial was initiated in Q1 2024; recruitment is ongoing in the US and UK. Sites in Belgium, Denmark, Spain, UK, and Japan are being activated in 2024.

Clinical trial identification

NCT06150183.

Editorial acknowledgement

Medical writing support provided by Kordula Heinen of BioNTech.

Legal entity responsible for the study

BioNTech SE.

Funding

BioNTech SE and Genmab A/S.

Disclosure

I. Melero: Financial Interests, Personal, Advisory Board: Agneus, Alligator Bioscience, AstraZeneca, BMS, BioLineRx, Boehringer Ingelheim, Boston Pharma, CRISPR Therapeutics, CatalYm GmbH, Crescendo Biologics, Curon BIopharmaceutical, EMD Serono, F-Star, Genentech, Genmab, Gossamer Bio, Highlight Therapeutics, Hookipa Pharma, HotSpot Therapeutics, Inc., ImmuneSensor Therapeutics, Inc., Janssen, MSD, Merus N.V., Monopteros Therapeutics, NOXXON Pharma AG, Numab, Phenomic Bio, Pieris Pharmaceuticals GmbH, Pierre Fabre, Roche, Sanofi, Senti Biosciences, Servier, Shattuck Labs, Third Rock Ventures; Financial Interests, Personal, Other, Consultant: PharmaMar; Financial Interests, Institutional, Coordinating PI: AstraZeneca, Roche, BMS, Genmab, Alligator. N.J. Lakhani: Financial Interests, Personal, Advisory Board: Innovent Biologics; Financial Interests, Personal, Advisory Board, Participation in Ad Board: Ikena, SK Life Sciences; Financial Interests, Institutional, Local PI: ALX Therapeutics, Ascentage, Constellation Pharma, Alpine Biosciences, Forty Seven, Merck, Pfizer, Regeneron, Symphogen, InhibRx, Seagen, Sapience Therapeutics, Jounce, Northern Biologics, Odonate, Loxo/Lilly, Ikena, Mersana Therapeutics, Astellas, Celgene, Helsinn, Shattuck Labs, Samumed, GSK, Alkermes, Samumed, Tizona Therapeutics, Gilead, Repare Therapeutics, Alkermes, InhibRx, Janssen, cytomX, KSQ Therapeutics, Repare Therapeutics, Arcus Bio, Artios, Revolution Medicines, Volastra; Financial Interests, Institutional, Coordinating PI: Servier. J. Powderly: Financial Interests, Personal, Other, Consulting: Boxer Capital; Financial Interests, Personal, Writing Engagement, Consulting: Aavocyte; Financial Interests, Personal, Member of Board of Directors, Founder and Owner: Carolina BioOncology Institute, PLlc, BioCytics Inc.; Financial Interests, Personal, Ownership Interest, Founder and Owner: BioCytics Inc.; Financial Interests, Personal, Ownership Interest, Founder and Owner of phase 1 cancer research clinic: Carolina BioOncology Institute, PLlc; Financial Interests, Personal, Other, Founder and Owner, developing intellectual property for cellular therapies: BioCytics Inc; Financial Interests, Personal and Institutional, Local PI: Bristol Myers Squibb, Cullinan, Genentech/Roche, AstraZeneca/MedImmune, EMD Serono, Macrogenics, InCyte, Top Alliance BioSciience, Seattle Genetics, AbbVie, FLX Bio, Alkermes, Arcus BioSciences, Tempest Therapeutics, Calico Life Sciences, Apros, Jounce Therapeutics, Atreca, Sequenom, Repertoire Immune Medicines, Molecular Templates, I-MAB Pharma, NexCure, Xilio Therapeutics, Immune-Onc, Trethera, Zenshine Pharma, Adagene, BJ BioScience, Fate Therapeutics, Conjupro BioTherapeutics, PEEL Therapeutics, CUE BioPharma, Pieris Pharmaceuticals, RiboScience, Moderna TX, Phanes Therapeutics, SK Life Science, Harbour BioMed, Simcere, Allarity, Aulos, GI Innovation, IGM BioSciences, Aptevo, Medikine, IconOVir Bio, Qurgen; Financial Interests, Institutional, Funding: Precision for Medicine, MT Group, Stemcell Technologies, Replimmune, Merck, Xilis; Financial Interests, Personal and Institutional, Funding: Pioma; Financial Interests, Personal and Institutional, Local PI, Also funding for contract laboratory services: Nuvation; Financial Interests, Personal and Institutional, Funding, Wugen is sponsor of contract laboratory translational research: Wugen; Financial Interests, Personal and Institutional, Other, AavoCyte & AavoBioCytics are jointly developing cellular therapies with BioCytics Human Applications Lab for point of care manufacturing: AavoCyte; Financial Interests, Personal and Institutional, Local PI, Clinical Trial funding: Glenmark; Financial Interests, Personal and Institutional, Local PI, Clinical Trial Funding: FBD Biologics, MBrace, Astellas, BioNTech, SK Life Sciences, Revolution Medicines, Multitude, Sairopa, Corbus, CytoMx, Apollo; Other, As Founder and Owner of BioCytics Inc. developing immune cellular therapy: BioCytics Inc. A.A. Adjei: Financial Interests, Institutional, Coordinating PI, funding for clinical trial: Vyriad; Non-Financial Interests, Advisory Role, uncompensated Advisory Board member: Merck AG, Cagent Pharmaceuticals; Non-Financial Interests, Advisory Role, uncompensated Chair of Advisors: Swiss Rockets; Non-Financial Interests, Principal Investigator, Clinical Trials: Kronos Bio; Non-Financial Interests, Principal Investigator, Climical Trials: BionTech, Bridge Bio; Other, Editor-in-Chief of Journal of Thoracic Oncology and JTO CRR: International Association for the Study of Lung Cancer. J.S. Lopez: Financial Interests, Personal, Advisory Board: Roche Genentech, Basilea, Ellipses Pharma, Cureteq, Pierre Faber, GSK; Financial Interests, Institutional, Research Grant: Roche Genentech, Basilea, Astex. L.G. Paz-Ares: Financial Interests, Personal, Advisory Board, Speaker fees: Roche, MSD, BMS, AZ, Lilly, PharmaMar, BeiGene, Daiichi, Medscape, PER; Financial Interests, Personal, Advisory Board: Merck Serono, Pfizer, Bayer, Amgen, Janssen, GSK, Novartis, Takeda, Sanofi, Mirati, Boehringer; Financial Interests, Personal, Other, Board member: Genomica, Altum sequencing; Financial Interests, Personal, Other, lectures: AICME; Financial Interests, Personal, Other, Lectures: CCO; Financial Interests, Personal, Member of Board of Directors, Board member: Stab Therapeutics; Financial Interests, Personal, Other, spinn off (I have stocks): Altum Sequencing; Financial Interests, Personal, Ownership Interest, spin-off (10%): Stab Therapeutics; Financial Interests, Institutional, Coordinating PI: Daiichi Sankyo, AstraZeneca, Merck Sharp & Dohme Corp, BMS, Janssen-Cilag International NV, Novartis, Roche, Sanofi, Tesaro, Alkermes, Lilly, Takeda, Pfizer, PharmaMar; Financial Interests, Personal, Coordinating PI: Amgen; Financial Interests, Other, Member: AACR, ASCO, ESMO; Financial Interests, Other, Foundation Board Member: AECC; Financial Interests, Other, President. ASEICA (Spanish Association of CancerResearch): ASEICA; Financial Interests, Other, Foundation president: ONCOSUR; Financial Interests, Other, member: Small Lung Cancer Group; Non-Financial Interests, Other, Board member of this anti-cancer Charity: AECC; Non-Financial Interests, Member, Past-President: ASEICA (Spanish Cancer Research Association); Non-Financial Interests, Leadership Role, President: Oncosur Foundation. I. Moreno Candilejo: Financial Interests, Personal, Advisory Board: Exafield Company, Ellipses Pharma; Financial Interests, Institutional, Invited Speaker: Medicine School, CEU University; Financial Interests, Personal and Institutional, Local PI: Ideal4rwe grant (Digicore consortium). F. Thistlethwaite: Financial Interests, Personal, Advisory Board, Ad board: BMS; Financial Interests, Personal, Advisory Board, Ad boards: GSK; Financial Interests, Personal, Advisory Board, Adboard/consultancy: T-Knife Therapeutics; Financial Interests, Personal, Advisory Board: Immatics, Scenic Biotech, F-Star, Leucid; Financial Interests, Personal, Invited Speaker: Kite Gilead; Financial Interests, Personal, Other, Occasional individual consulting: Guidepoint; Financial Interests, Personal, Advisory Board, Advisory board meeting Feb 2023: CytomX; Financial Interests, Personal, Advisory Board, Advisory board Feb 2024: Grey Wolf Therapeutics; Financial Interests, Institutional, Other, iMATCH is a consortium funded by not for profit Innovate UK (UK government body) partners include clinical and academic institutes. I am director and my salary (0.2WTE) is supported through this work as a grant to my institution (The Christie NHS foundation trust - not for profit NHS Hospital) from IUK: iMATCH director; Financial Interests, Institutional, Local PI, NCT02890069: Novartis; Financial Interests, Institutional, Research Grant, Sarcoma pathways project and CAR-T PROMs study: GSK; Financial Interests, Institutional, Local PI, NCT02493751: Pfizer; Financial Interests, Institutional, Local PI, NCT03245736, NCT02988817, NCT02552121, NCT02001623, NCT05180474: GenMab; Financial Interests, Institutional, Local PI, NCT02277717: Synthon; Financial Interests, Institutional, Local PI, NCT03013491: CytomX; Financial Interests, Institutional, Local PI, NCT03314935: Incyte; Financial Interests, Institutional, Local PI, NCT02908906 and CAR-T referrals project: Janssen; Financial Interests, Institutional, Local PI, NCT03132792, NCT04044768: Adaptimmune; Financial Interests, Institutional, Local PI, NCT03400332: BMS; Financial Interests, Institutional, Local PI, NCT04262466, NCT03973333, NCT03515551: Immunocore; Financial Interests, Institutional, Local PI, EudraCT Number: 2018-001005-85, 2018-003446-16: Achilles ltd; Financial Interests, Institutional, Local PI: Agalimmune Ltd; Financial Interests, Institutional, Local PI, NCT02834247: Millenium Pharmaceuticals/Takeda; Financial Interests, Institutional, Local PI, NCT02690350: Daiichi Sankyo; Financial Interests, Institutional, Local PI, NCT04839991: Crescendo; Financial Interests, Institutional, Local PI, NCT05104515: Oxford Vacmedix Ltd; Financial Interests, Institutional, Local PI, NCT05278975: RS Oncology Llc; Financial Interests, Institutional, Coordinating PI, NCT03697824, NCT03391778: GSK; Financial Interests, Institutional, Coordinating PI, NCT04140500, NCT04857138, NCT04826003: Roche; Financial Interests, Personal, Coordinating PI, NCT05008913, NCT04949425, NCT0331509, NCT03313557: AstraZeneca; Financial Interests, Institutional, Coordinating PI, NCT03829501: Kymab Ltd/Sanofi; Financial Interests, Institutional, Coordinating PI, EudraCT 2019-003329-11: Chugai; Financial Interests, Institutional, Coordinating PI, NCT05430555: T-Knife Therapeutics; Financial Interests, Institutional, Coordinating PI, NCT03621982: ADCT Therapeutics; Financial Interests, Institutional, Research Grant, IRAS Project ID: 227414: Novartis; Financial Interests, Institutional, Coordinating PI, ITIL-306-202: Instil Bio; Financial Interests, Institutional, Funding, CAR-T referrals project: Gilead, Autolus; Financial Interests, Institutional, Local PI, NCT04763083: Novalgen; Financial Interests, Institutional, Local PI, NCT05714553: Nucana; Non-Financial Interests, Other, Panel member for a funding committee (MRC is a UK government NFP organisation) 2020-2024: MRC DPFS panel member; Non-Financial Interests, Advisory Role, Sarcoma UK is a not-for-profit charity. I act as an advisor on their Research Strategy Committee. This role is not compensated: Sarcoma UK; Non-Financial Interests, Leadership Role, Funding is from not-for-profit government bodies, Role is not compensated: Chair of the Independent Steering Committee for NIHR Blood & Transplant Research Unit, Oxford; Non-Financial Interests, Advisory Role, Funding panel member for CRUK (not-for profit charity), Role is not compensated: CRUK New Agents Committee Member; Non-Financial Interests, Leadership Role, Chair of Cell therapy subgroup. MRC is a not-for-profit organisation. Role is not compensated: MRC Advanced Therapies Task Group; Non-Financial Interests, Leadership Role: ESMO Congress 2024 Experimental Immunotherapy Track Chair; Non-Financial Interests, Advisory Role: ESMO TAT conference scientific advisory board 2025; Non-Financial Interests, Advisory Role, Target Ovarian Cancer is a not-for-profit charity, I am Chair of their Scientific Advisory board, This role is not compensated: Target Ovarian Cancer. K.S. Rohrberg: Financial Interests, Personal, Invited Speaker: Bayer, Amgen, MSD, GSK; Financial Interests, Personal, Advisory Board: AbbVie, Genmab; Financial Interests, Institutional, Coordinating PI, Compensation for conduction of clinical trial: Lilly, Roche/Genentech, Bristol Myers Squibb, Symphogen, Pfizer, Novartis, Alligator Bioscience, Genmab, Bioinvent, Monta Bioscience, Navire; Financial Interests, Institutional, Other, Compensation for conduction of clinical trial: Bayer, Incyte, Puma Biotechnology, Orion Clinical; Financial Interests, Institutional, Local PI, Compensation for conduction of clinical trial: Amgen. G. Jerusalem: Financial Interests, Personal, Advisory Board: Novartis, Roche, Pfizer, BMS, Lilly, AstraZeneca, Daiichi Sankyo; Financial Interests, Personal, Invited Speaker: Novartis, Pfizer, BMS, Lilly, AstraZeneca, Seagen; Financial Interests, Personal, Steering Committee Member: Novartis, AZ/Daiichi Sankyo, BMS; Financial Interests, Institutional, Local PI: Novartis, Roche, Syneos Health, Iqvia, TRIO, Bayer, MSD, IBCSG, PRA, Eli Lilly, PPD, Theradex, ABCSG, Modra, AstraZeneca, Odonate Therapeutics, BMS, ICON, Boeringer, Quintiles, Pfizer, Lilly, Daiichi Sankyo, Seagen, Medimmune; Non-Financial Interests, Member: ASCO, BSMO; Other, Medical writer support: Novartis, Lilly, BMS, AstraZeneca; Other, Support for attending meetings and/or travel: Novartis, Lilly, BMS, Roche, AstraZeneca, Pfizer. A. Malmberg: Financial Interests, Personal, Full or part-time Employment, Biostatistician: Genmab A/S; Financial Interests, Personal, Stocks/Shares: Genmab A/S. A. Ioan-Facsinay: Financial Interests, Personal, Full or part-time Employment, I am an employee of Genmab: Genmab; Financial Interests, Personal, Stocks/Shares: Genmab, J&J. P.J. Upadhyay: Financial Interests, Personal, Full or part-time Employment: Genmab b.v. B. Tan: Financial Interests, Personal, Full or part-time Employment: BioNTech US; Financial Interests, Personal, Stocks/Shares: Pfizer, Eli Lilly, AbbVie, Regeneron, Novo Nordisk, Moderna, Vertex. R. Bartz: Financial Interests, Personal, Full or part-time Employment: BioNTech SE. T.B.B. Gaziel: Financial Interests, Institutional, Stocks/Shares, Long term incentives -Shares: Genmab; Non-Financial Interests, Project Lead, Medical Director in Genmab involved in trial design and strategy: Genmab; Non-Financial Interests, Institutional, Proprietary Information: Genmab. U. Forssmann: Financial Interests, Personal, Full or part-time Employment, Employee of Genmab A/S since 2015: Genmab A/S; Financial Interests, Personal, Stocks/Shares, Employee of Genmab A/S since 2015: Genmab A/S; Non-Financial Interests, Personal, Proprietary Information, Employee of Genmab A/S since 2015: Genmab A/S. I. Celik: Financial Interests, Personal, Full or part-time Employment: BioNTech SE; Financial Interests, Personal, Stocks/Shares: BioNTech SE; Financial Interests, Personal, Other, Honoraria: BioNTech SE, Merck KGaA; Other, Personal, Other, Patents: Merck KGaA. C. Gann: Financial Interests, Personal, Full or part-time Employment: BioNTech SE; Financial Interests, Personal, Stocks/Shares: BioNTech SE, Merck KGaA; Other, Personal, Other, Patents: Merck KGaA. L. De Mattos-Arruda: Financial Interests, Personal, Invited Speaker, Speaker bureau: Roche; Financial Interests, Personal, Full or part-time Employment: BioNTech SE; Financial Interests, Personal, Stocks/Shares: BioNTech; Financial Interests, Institutional, Research Grant, Research collaboration grant: NanoString Technologies; Other, Education grant: BMS.