1079TiP - A phase I first-in-human study of PRTH-101, an IgG1 monoclonal antibody targeting DDR1, as a monotherapy and combined with pembrolizumab in patients with advanced solid malignancies

Background

Discoidin domain receptor 1 (DDR1) is a collagen receptor that represents a promising therapeutic target due to its role in excluding lymphocytes from the tumor microenvironment (TME) by aligning collagen fibers. DDR1 expression is high in multiple cancer types and associated with worse survival. DDR1 activity-driven RNA signatures are associated with poor responses to PD-1 inhibition. PRTH-101 is a humanized IgG1 antibody that binds to the extracellular domain of both membrane-bound and soluble DDR1. In preclinical models, PRTH-101 monotherapy resulted in disruption of aligned collagen fibers in the tumor stroma, increased infiltration of lymphocytes, and tumor growth inhibition. When PRTH-101 is combined with PD-1 inhibition, activated T cell infiltration is increased compared to PRTH-101 alone. These data provide a strong rationale for evaluating PRTH-101 as monotherapy and in combination with PD-1 blockade in multiple indications.

Trial design

This is a phase 1, first-in-human study that will evaluate intravenous PRTH-101 +/- pembrolizumab in patients with advanced solid tumors, The first part seeks to identify the maximum tolerated dose (MTD) or optimal biologic dose (OBD), of PRTH-101 to determine the recommended phase 2 dose (RP2D). Biomarker backfill cohorts of 10 additional patients each are planned for the two highest dose cohorts to aid biomarker correlation with dose and response. The second part seeks to identify the MTD or OBD of PRTH-101 in combination with pembrolizumab to determine the PRTH-101 combination RP2D. Both parts will use a Bayesian Optimal Interval design. A third part consists of dose expansion in disease-directed cohorts to assess the anti-tumor efficacy of PRTH-101 monotherapy and/or combination therapy in up to 40 patients per cohort in a Bayesian Optimal Phase 2 design with prespecified stopping boundaries based on objective response rates. Safety, efficacy, pharmacokinetic, and pharmacodynamic endpoints will be monitored and reported. DDR1 expression levels on tumors, circulating DDR1, molecular and cellular changes in the TME, and changes on CD8 PET imaging will also be assessed.

Clinical trial identification

NCT05753722, 03MAR2023.

Editorial acknowledgement

Legal entity responsible for the study

Parthenon Therapeutics.

Funding

Parthenon Therapeutics.

Disclosure

S. Sen: Financial Interests, Institutional, Local PI: Parthenon Therapeutics. A.I. Spira: Financial Interests, Personal, Other, Consulting or Advisory Role: Incyte, Mirati Therapeutics, Gritstone Oncology, Jazz Pharmaceuticals, Janssen Research & Development, Mersana, Gritstone Bio, Daiichi Sankyo/AstraZeneca, Array Biopharma, Blueprint Medicines; Financial Interests, Personal, Other, Consulting or Advisory Role / Honoraria: Amgen, Novartis, Takeda, AstraZeneca/MedImmune, Merck, Bristol Myers Squibb; Financial Interests, Personal, Other, Honoraria: CytomX Therapeutics, Janssen Oncology, Bayer; Financial Interests, Institutional, Officer, CEO: NEXT Oncology Virginia; Financial Interests, Personal, Stocks/Shares: Eli Lilly; Financial Interests, Institutional, Local PI: LAM Therapeutics, Roche, AstraZeneca, Boehringer Ingelheim, Astellas Pharma, MedImmune, Novartis, Newlink Genetics, Incyte, AbbVie, Ignyta, Trovagene, Takeda, Macrogenics, CytomX Therapeutics, Astex Pharmaceuticals, Bristol Myers Squibb, Loxo, Arch Therapeutics, Gritstone, Plexxikon, Amgen, Daiichi Sankyo, ADCT, Janssen Oncology, Mirati Therapeutics, Rubius, Synthekine, Mersana, Blueprint Medicines, Kezar, Revolution Med. D. Sommerhalder: Financial Interests, Personal, Other, Ad-hoc advisory role: Syneos SAG; Financial Interests, Personal, Other, Medical consulting: Guidepoint; Financial Interests, Institutional, Full or part-time Employment, Employed as a physician by Texas Oncology, a for-profit entity.: Texas Oncology/US Oncology; Financial Interests, Institutional, Local PI: Astellas, Biomea Fusion, Boehringer Ingelheim, BJ Biosciences, BioNTech, Fate Therapeutics, Gilead Sciences, Immuneering, Kura Oncology, Monopteros Therapeutics, Navire, Nimbus Saturn, NGM Biopharmaceuticals, Parthenon, Pfizer, Revolution Medicines, Mirati Therapeutics, Symphogen, Teon Therapeutics, MediLink Therapeutics, ZielBio. F. Meric-Bernstam: Financial Interests, Personal, Other, Consultant: AstraZeneca, F. Hoffman-La Roche Ltd., Zymeworks, OnCusp Therapeutics; Financial Interests, Personal, Advisory Board, Advisory Board/Consultant: Seagen; Financial Interests, Personal, Advisory Board: Zentalis, Karyopharm, Biovica, Eisai, Protai, TheraTechnologies; Financial Interests, Personal, Other, Consulting: Tallac Therapeutics, Lengo Therapeutics, Loxo-Oncology, Black Diamond, Infinity Pharmaceuticals, AbbVie, GT Aperion, Ecor1; Financial Interests, Personal, Other, Consutling: Menarini Group; Financial Interests, Institutional, Other, Local PI / Research Grant: Aileron Therapeutics, Bayer Healthcare, CytomX Therapeutics Inc., Daiichi Sankyo Co. Ltd., eFFECTOR Therapeutics, Taiho Pharmaceutical Co.; Financial Interests, Institutional, Other, Local PI / Research Grant / Coordinating PI: AstraZeneca; Financial Interests, Institutional, Local PI: Calithera Biosciences, Curis Inc., Debiopharm International, Guardant Health Inc., Klus Pharma, Novartis; Financial Interests, Institutional, Other, Local PI / Steering Committee Member: Genentech Inc.; Financial Interests, Institutional, Research Grant: Takeda Pharmaceutical Co., Puma Biotechnology Inc., Repare; Other, Other, Travel support: European Organisation for Research and Treatment of Cancer (EORTC), European Society for Medical Oncology (ESMO); Other, Other, Travel Support: Cholangiocarcinoma Foundation. J.D. Berlin: Financial Interests, Personal, Advisory Board: Merck KGA, mirati, merus, bristol Meyers, bexion, ipsen, merck, sharp, dohme, biosapien, insmed, Oxford biotherapeutics; Financial Interests, Institutional, Local PI: Astellas, atreca, bayer, BMS, dragonfly, I-MAB, transient therapeutic, totus, Tyra, Sumitomo Dainippon Pharma Oncology, 23 and Me, strata, Eli Lilly, hibercell; Other, Other, DSMB member: AstraZeneca, novocure, I-SPY. M. Cecchini: Financial Interests, Personal, Advisory Board, Honoraria for advisory board: Eisai Co, Agios Pharmaceuticals, DAVA Oncology, BAYER Pharmaceuticals, Seattle Genetics, Macrogenics, Taiho, Daiichi Sankyo, AstraZeneca; Financial Interests, Personal, Stocks/Shares, Stock options for advisory role: Parthenon Therapeutics. R.E. Sanborn: Financial Interests, Personal, Advisory Board: AstraZeneca, EMD Serono, Daiichi Sankyo, Lilly Oncology, Janssen Oncology, Macrogenics, Sanofi Aventis, Regeneron, Mirati Therapeutics, GSK, G1 Therapeutics; Financial Interests, Personal, Invited Speaker: Illumina; Financial Interests, Personal, Steering Committee Member: GSK, Janssen Oncology; Financial Interests, Institutional, Funding, Funding for investigator-sponsored trial: Merck, AstraZeneca; Financial Interests, Institutional, Other, Institutional research support: BMS; Financial Interests, Institutional, Funding, Clinical trial funding: Jounce. G.E. Peoples: Financial Interests, Personal and Institutional, Advisory Role: Parthenon Therapeutics. T. Schürpf: Financial Interests, Personal, Full or part-time Employment: Parthenon Therapeutics. L.A. Dillon: Financial Interests, Personal, Full or part-time Employment: Parthenon Therapeutics. G.T. Clifton: Financial Interests, Personal, Full or part-time Employment: Parthenon Therapeutics. J.P. Eder: Financial Interests, Personal, Full or part-time Employment: Parthenon Therapeutics. A.W. Tolcher: Financial Interests, Personal and Institutional, Coordinating PI: Parthenon Therapeutics. All other authors have declared no conflicts of interest.