Abstract 780TiP
Background
The major histocompatibility complex (MHC) class I-related proteins MICA and MICB are surface glycoproteins that are up-regulated in response to stress and are widely expressed on human tumors. MICA/MICB are ligands for the activating receptor, Natural Killer Group 2 member D (NKG2D), expressed on NK cells, CD8+ T cells, γδ T cells and iNKT cells. Proteases in the tumor microenvironment cleave MICA/MICB from the cell surface thus enabling immune evasion. Increased concentrations of shed MICA have been observed in serum from patients across multiple tumor types and correlate with poor survival. CLN-619 is a humanized IgG1 monoclonal antibody that prevents the proteolytic release of MICA/MICB to allow immune destruction of tumor cells through both NKG2D-mediated and antibody-dependent cell-mediated cytotoxicity. The antibody has been shown to restore the MICA/MICB-NKG2D axis to promote NK-mediated tumor cell lysis (AACR Annual Meeting abstract 3506, April 2022).
Trial design
This is a global, multi-center dose-escalation study of CLN-619 as monotherapy and in combination with pembrolizumab. Key eligibility criteria include 1) histological or cytological diagnosis of cancer and 2) refractory metastatic disease, or locally advanced disease not amenable to local therapy 3) normal laboratory parameters or within grade 1 CTCAE toxicity levels. The study explores ascending intravenous dose levels of CLN-619 as monotherapy and in combination with pembrolizumab in 21-day cycles. At the respective RP2D, CLN-619 monotherapy and the combination of CLN-619 and pembrolizumab will be evaluated in disease-specific expansion cohorts in select tumor types. Serum levels of soluble MICA/MICB, identity of MICA/MICB alleles, phenotypes of peripheral blood mononuclear cells, cytokines and paired tumor biopsies will be investigated for correlative pharmacodynamic and predictive biomarkers. This clinical trial is in progress.
Clinical trial identification
NCT05117476.
Editorial acknowledgement
Legal entity responsible for the study
Cullinan Oncology, LLC.
Funding
Cullinan Oncology, LLC.
Disclosure
E.P. Hamilton: Financial Interests, Institutional, Consulting/Advisory Role: Genentech/Roche, Boehringer Ingelheim, Novartis, Dantari, Lilly, Merck, Puma Biotechnology, Silverback Therapeutics, CytomX, Pfizer, Mersana, Black Diamond, H3 Biomedicine, Daiichi Sankyo, AstraZeneca, Arvinas, Deciphera Pharmaceuticals, Eisai, Seagen, Arcus, iTeos, Janssen, Loxo, Relay Therapeutics; Financial Interests, Institutional, Research Grant: Oncomed, Genentech/Roche, Zymeworks, Rgenix, Arqule, Clovis, Silverback Therapeutics, Millenium, Acerta Pharma, Sermonix Pharmaceuticals, Black Diamond, Karyopharm, Curis, Syndax, Novartis, Boehringer Ingelheim, Immunomedics, FujiFilm, Taiho, Deciphera, Fochon, Molecular Templates, Onconova Therapeutics, Dana Farber Cancer Hospital, Hutchinson MediPharma, MedImmune, SeaGen, Compugen, TapImmune, Lilly, Pfizer, H3 Biomedicine, Merus, Regeneron, Arvinas, StemCentRx, Verastem, Effector Therapeutics, CytomX, InventisBio, Lycera, Mersana, Radius Health, AbbVie, Nucana, Leap Therapeutics, Zenith Epigenetics, Harpoon, Orinove, AstraZeneca, Tesaro, Macrogenics, EMD Serono, Daiichi Sankyo, Syros, Sutro, G1 Therapeutics, Merck, PharmaMar, Olema, Immunogen, Plexxicon, Amgen, Akesobio Australia, Shattuck Labs, ADC Therapeutics, Aravive, Atlas MedX, Ellipses, Incyte, Jacobio, Mabspace Biosciences, Myraid Genetic Labs, Oric Pharmaceuticals, Pieris Pharmaceuticals, Pionyr Immunotherapeutics, Repertoire Immune Medicine, Treadwell Therapeutics, Vincerx Pharma. I. Melero: Financial Interests, Personal, Advisory Board: Gossamer Bio, Highlight Therapeutics, MSD, Alligator Bioscience, Genmab, Numab, Noxxon Pharma AG, BMS, CRISPR Therapeutics, Genentech, AstraZeneca, Boehringer Ingelheim, EMD Serono, Roche; Financial Interests, Personal, Other, Consultant: Pharma Mar; Financial Interests, Institutional, Invited Speaker: AstraZeneca, Roche, BMS, Genmab, Alligator. I. Lugowska: Financial Interests, Personal, Invited Speaker, The reports of clinical trials.: ROCHE, BMS, Macrogenics, Amgen; Financial Interests, Institutional, Research grants: ROCHE; Financial Interests, Institutional, Research Grant: Agenus; Financial Interests, Personal and Institutional, Invited Speaker: Agenus, Roche, BMS, Janssen, AstraZeneca, Incyte, Macrogenics, Checkpoint Inhibitors, Celon, Pfizer, MSD, Debio; Non-Financial Interests, Project Lead: MSCI; Non-Financial Interests, Advisory Role, Board Member: EORTC. A.M. Arance Fernandez: Financial Interests, Personal, Advisory Board, Consultant /Advisory/ Speaker / Travel, Accommodations, Expenses: Pierre Fabre, Novartis, Roche, BMS, MSD, Merck, Sanofi; Financial Interests, Institutional, Research Funding: Pierre Fabre, Novartis, MSD, BMS, Merck, Roche, Sanofi, Amgem. L. Vila Martinez: Financial Interests, Personal, Advisory Board: Roche, AstraZeneca; Financial Interests, Personal, Invited Speaker: Merck, Roche, BMS, Pfizer. J.D. Powderly: Financial Interests, Personal, Consulting: Boxer Capital; Financial Interests, Personal, Invited Speaker, Consulting: Aavocyte; Financial Interests, Personal, Invited Speaker, 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, Founder and Owner, developing intellectual property for cellular therapies: BioCytics Inc; Financial Interests, Personal and Institutional, Invited Speaker: 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; 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, Invited Speaker, Also funding for contract laboratory services: Nuvation; As Founder and Owner of BioCytics Inc. developing immune cellular therapy.: BioCytics Inc.. M. Gutierrez: Financial Interests, Personal, Invited Speaker: Guardant Health; Financial Interests, Personal, Stocks/Shares: Cota Healthcare; Financial Interests, Institutional, Invited Speaker: Merck, BMS, Incyte, NexCure, Pfizer, Roche/Genentech, Boehringer Ingelheim, GSB Pharma, Moderna, Eisai, Silenseed, Seattle Genetics, Regeneron, Sanofi, Johnson & Johnson, MedImmune, Checkpoint Therapeutics, Acerta Pharmaceuticals, Arcus Biosciences, Array BioPharma, Bayer, Celgene, Compass Therapeutics, Constellation Pharmaceuticals, Cyter, EMD Sereno, Fate Therapeutics, GlaxoSmithKline, Infinity, Pharmacyclics, Synlogic, Tesaro, Vedanta. T. Serino: Financial Interests, Institutional, Full or part-time Employment, I currently work in Clinical Research for Cullinan.: Cullinan Oncology; Financial Interests, Institutional, Full or part-time Employment, I previously worked in Clinical Research for Keros: Keros Therapeutics. N. Mehta: Financial Interests, Personal, Full or part-time Employment: Cullinan Oncology; Financial Interests, Personal, Stocks/Shares: Cullinan Oncology; Financial Interests, Personal, Filed patents: Cullinan Oncology. I. Shapiro: Financial Interests, Personal, Full or part-time Employment: Cullinan Oncology; Financial Interests, Personal, Stocks/Shares: Cullinan Oncology, Agenus. K. Whalen: Financial Interests, Institutional, Full or part-time Employment, I am a full time employee of Cullinan Oncology: Cullinan Oncology; Financial Interests, Institutional, Stocks/Shares, Stocks/ options/shares: Cullinan Oncology; Financial Interests, Institutional, Patents: Tarveda Therapeutics, Aveo Oncology. J. Michaelson: Financial Interests, Institutional, Full or part-time Employment, Full time employee: Cullinan Oncology; Financial Interests, Institutional, Stocks/Shares: Cullinan Oncology, Jounce Therapeutics. J. Jones: Financial Interests, Personal, Officer, Chief Medical Officer: Cullinan Oncology; Financial Interests, Personal, Stocks/Shares: Cullinan Oncology. J.E. Janik: Financial Interests, Personal, Full or part-time Employment, Vice-President Clinical Development: Cullinanoncology; Financial Interests, Personal, Stocks/Shares: Cullinanoncology. V. Moreno Garcia: Financial Interests, Personal, Advisory Board: BMS, Janssen, Roche, Basilea, Bayer; Financial Interests, Personal, Full or part-time Employment: START; Non-Financial Interests, Principal Investigator, AbbVie, AceaBio, Adaptimmune, ADC Therapeutics, Aduro, Agenus, Amcure, Amgen, Astellas, AstraZeneca Bayer Beigene BioInvent International AB, BMS, Boehringer, Boheringer, Boston, Celgene, Daichii Sankyo, Debiopharm ,Eisai, e-Terapeutics, Exelisis, Forma Therapeutics, Genmab, GSK, Harpoon, Hutchison, Immutep, Incyte, Inovio, Iovance, Janssen, Kyowa Kirin, Lilly, Loxo, MedSir, Menarini, Merck, Merus, Millennium, MSD, Nanobiotix, Nektar, Novartis, Odonate Therapeutics, Pfizer, Pharma Mar, PharmaMar, Principia, PsiOxus, Puma, Regeneron, Rigontec, Roche, Sanofi, Sierra Oncology, Synthon, Taiho, Takeda, Tesaro, Transgene, Turning Point Therapeutics, Upshersmith.: Multiple.