1034P - Phase I/II dose escalation and dose expansion study of TransCon IL-2 β/γ alone or in combination with pembrolizumab: Determination of recommended phase II dose (RP2D) for monotherapy

Background

TransCon IL-2 β/γ is a novel prodrug with sustained release of an IL-2 analog (IL-2 β/γ). It is created by permanently attaching a 5 kDa mPEG in the IL-2Rα binding site and transiently attaching this IL-2 β/γ to an mPEG carrier molecule via a TransCon Linker creating a prodrug and improving pharmacokinetics (PK). The key objectives of the IL-Believe trial are to evaluate safety/tolerability, define the maximum tolerated dose and RP2D of TransCon IL-2 β/γ alone or in combination with pembrolizumab.

Methods

Patients age ≥18 with advanced solid tumors receive TransCon IL-2 β/γ IV as monotherapy or in combination with pembrolizumab IV every 3 weeks. Disease is assessed every 9 weeks per RECIST 1.1. Safety, PK, and pharmacodynamics (PD) are evaluated.

Results

As of 28 April 2023, 25 patients were treated with monotherapy (20 to 160 mcg/kg) and 14 in combination (20 to 80 mcg/kg). One Dose Limiting Toxicity of Grade 3 (G3) Cytokine Release Syndrome was reported at 160 mcg/kg monotherapy. No grade 3 or higher treatment related adverse event was reported at the RP2D (120 mcg/kg). PK results showed systemic drug exposure of TransCon IL-2 β/γ with a half-life of at least 35 hours. PD data suggested sustained activation and dose dependent expansion of cytotoxic effector cells while Tregs were expanded minimally. Absolute lymphocyte counts increased in a dose dependent manner while eosinophil counts remained low. Preliminary antitumor efficacy was observed in monotherapy, including 1 unconfirmed partial response (MSI-h CRC, progressed on prior anti-PD1) at 120 mcg/kg and >45 weeks of stable disease in 1 patient with pancreatic cancer at 80 mcg/kg, both continuing with treatment. The monotherapy RP2D was determined to be 120 mcg/kg.

Conclusions

TransCon IL-2 β/γ is generally well-tolerated as monotherapy and in combination with pembrolizumab. The RP2D for monotherapy was determined at 120 mcg/kg IV every 3 weeks while dose escalation continues for combination therapy. PK data indicated a half-life of at least 35 hours and PD data confirm durable activation and expansion of cytotoxic immune cells from TransCon IL-2 β/γ.

Clinical trial identification

NCT05081609.

Editorial acknowledgement

Legal entity responsible for the study

Ascendis Pharma.

Funding

Ascendis Pharma.

Disclosure

S. Kim: Financial Interests, Personal, Advisory Board: Novartis, AstraZeneca, Lilly, DaeHwa Pharma, ISU Abx, Daiichi-Sankyo, BeiGene, HLB Life Science, Samsung Bioepics, OBI pharma; Financial Interests, Personal, Invited Speaker: Legochem Bioscience; Financial Interests, Personal, Ownership Interest: Genopeaks, Neogene TC; Financial Interests, Institutional, Research Grant: Novartis, Sanofi-Genzyme, DongKook Pharm Co. D. Davar: Other, Research Funding: Arcus, CellSight Technologies, GSK, Merck, Checkmate Pharmaceuticals, Zucero Therapeutics; Other, Other, Travel, Accomodations: Castle Biosciences; Other, Speaker’s Bureau: Castle Biosciences; Other, Other, Consulting role: Clinical Care Options; Other, Other, Consulting Role: Finch Therapeutics, Gerson Lehrman Group, Medical Learning Group, Xilio Therapeutics. 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; Other, Other, As Founder and Owner of BioCytics Inc. developing immune cellular therapy.: BioCytics Inc.. A.G. Hill: Other, Stocks/Shares: Tasman Oncology. O. Yeku: Non-Financial Interests, Principal Investigator: Ascendis Pharma A/S, Avenge Bio, Inc, Immunocore Limited, Duality Biologics, Merck Sharp & Dohme Corporation, Pionyr Immunotherapeutics Inc, ProfoundBio; Other, Research Grant: Department of Defense; Other, Other, Consulting fees: Celldex Therapeutics, GIMV NV, Tiga Tx Inc; Other, Advisory Board: hc Bioscience. N. Gabrail: Other, Advisory Board, Honoraria: Pharmacosmos; Financial Interests, Other, Honoraria: Cardinal Health; Financial Interests, Advisory Board: Clinchoice. All other authors have declared no conflicts of interest.