679TiP - Cancer Research UK phase I/IIa trial of the prostaglandin E2 (PGE2) receptor 4 (EP4) antagonist HTL0039732 as monotherapy and in combination with immunotherapy in patients (pts) with advanced solid tumors

Background

EP4 is a Gs protein coupled receptor expressed on the surface of tumor cells, fibroblasts and immune cells within the tumor stroma. The prostanoid ligand PGE2 is secreted by immunosuppressive cells within the tumor microenvironment (TME) as well as by tumor cells and plays a critical role in suppression of innate and adaptive antitumor immune responses. HTL0039732 is a highly specific, potent small molecule antagonist of EP4, reversing PGE2-induced differentiation towards M2-like macrophages. HTL0039732 has demonstrated antitumor efficacy in preclinically relevant syngeneic tumor models, with evidence of significant synergy between HTL0039732 and blockade of the PD-1/PD-L1 pathway.

Trial design

This is a first-in-human trial to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics and antitumor activity of HTL0039732 as monotherapy and in combination with atezolizumab, in pts with advanced solid tumors. Eligible pts are aged ≥18 years; resistant or refractory to standard therapy; ECOG performance status 0/1; and have adequate renal, hepatic and bone marrow function. Phase I (dose escalation) consists of a parallel Part A (monotherapy) and Part B (combination with atezolizumab) using intra-patient dosing comparisons and a shared Bayesian Logistic Regression Model with overdose control (planned dose levels: 80,160, 320 and 640 mg orally QD; 21 day cycles). Lead indications currently proposed include microsatellite stable colorectal, gastro-oesophageal, castration-resistant prostate and squamous cell head and neck cancers. Phase IIa (expansion phase with an interim analysis) will evaluate the combination of HTL0039732 and atezolizumab in up to four of these tumor types. Correlative studies to determine target engagement will include mandatory paired tumor biopsies in Phase I Part B and Phase IIa to evaluate tumor T cell infiltration and correlation with participant response, together with TME and peripheral blood immunophenotyping. As of May 2024, three dose levels within Phase I Part A have been completed without DLT and recruitment to Phase I Part B has commenced.

Clinical trial identification

NCT05944237.

Editorial acknowledgement

Legal entity responsible for the study

Cancer Research UK.

Funding

Cancer Research UK.

Disclosure

D. Sarker: Financial Interests, Personal, Advisory Board: Eisai, Ipsen, Bayer, Surface Oncology, AAA, AbbVie, Boehringer Ingelheim, AstraZeneca, Incyte; Financial Interests, Personal, Invited Speaker: MSD, Bayer, AstraZeneca, Eisai, Servier, Incyte; Financial Interests, Personal, Other, Travel and conference fees: Ipsen; Financial Interests, Personal, Other, Travel and Conference Fees: MiNA Therapeutics; Financial Interests, Institutional, Coordinating PI: UCB, MiNA Therapeutics; Financial Interests, Institutional, Local PI: Eisai, Medivir AB, MSD, Bayer, RedX, GSK, Starpharma, Adaptimmune, Blueprint, H3, Regeneron, Taiho, AstraZeneca, Ipsen; Financial Interests, Institutional, Funding: Roche, Inspirata; Non-Financial Interests, Advisory Role: Medivir, UCB, MiNA Therapeutics. N. Cook: Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Institutional, Local PI: Taiho, Roche, AstraZeneca, Avacta, Bayer, Eisai, UCB, Boeringher, Stemline; Financial Interests, Institutional, Coordinating PI: RedX, Orion, Starpharma, Loxo Oncology; Non-Financial Interests, Advisory Role: Roche; Non-Financial Interests, Other, Committee chair: Cancer Research UK. D. Howe, N. Swain: Financial Interests, Personal, Full or part-time Employment: Sosei Heptares. N. Austin: Financial Interests, Personal, Full or part-time Employment: Sosei Heptares; Financial Interests, Personal, Stocks or ownership: Sosei Heptares. I.P. Leader: Financial Interests, Personal, Full or part-time Employment, Pharmaceutical development consultancy: IPL Pharma Services Limited. A. Manage: Financial Interests, Personal, Full or part-time Employment: Sosei Heptares; Financial Interests, Personal, Stocks/Shares: Sosei Heptares. A. Azizi: Financial Interests, Personal, Full or part-time Employment: Sosei Heptares; Financial Interests, Personal, Stocks or ownership: Unison; Financial Interests, Personal, Royalties: Sosei Heptares; Financial Interests, Personal, Speaker, Consultant, Advisor: Unison. D. Paisley: Financial Interests, Personal, Stocks or ownership: Novartis, Alcon. S.N. Symeonides: Financial Interests, Institutional, Advisory Board: Ellipses, Medannex, Eisai, MSD, Pfizer, Merck Serono, Duke Street Bio, Exscientia, Grey Wolf Therapeutics, Roche; Financial Interests, Institutional, Invited Speaker: Ipsen, MSD, Roche, Eisai; Financial Interests, Institutional, Other, Independent Data/Safety Monitoring: Valley Health, Exscientia, Grey Wolf Therapeutics; Financial Interests, Institutional, Full or part-time Employment, Medical Advisor in CRUK's Cente for Drug Development: Cancer Research UK (charity); Financial Interests, Institutional, Research Grant: MSD, Verastem; Financial Interests, Institutional, Coordinating PI: MSD, BioNTech, Nouscom; Financial Interests, Institutional, Steering Committee Member: Roche, Nucana, Sapience Therapeutics, BioLineRx, Boston Pharmaceuticals, Sierra Oncology, Incyte, Scancell, Medannex; Non-Financial Interests, Member of Board of Directors, Non-profit organisation connecting stakeholders in cancer drug development: Cancer Drug Development Forum; Other, Conference attendance (no personal gain): Ipsen, EUSA, MSD, BioNTech. B. Basu: Financial Interests, Personal, Advisory Board, Member of iDMC,I waiver all fees to University of Cambridge via Cambridge Enterprise, the Consultancy arm of the University of Cambridge: Genmab A/S; Financial Interests, Personal, Advisory Board, I waiver all fees to University of Cambridge via Cambridge Enterprise, the Consultancy arm of the University of Cambridge: Eisai Europe Limited, Roche; Financial Interests, Institutional, Research Grant, Grant funding for investigator-initated academic clinical trial: Varsity Pharma; Financial Interests, Institutional, Research Grant, Grant funding for investigator-initiated academic clinical trial: Celgene; Financial Interests, Institutional, Local PI, Contracted clinical trial: Incyte, Merck, AstraZeneca, Bicycle Therapeutics, Exact Therapeutics, MiNa Therapeutics, Corbus Therapeutics; Financial Interests, Institutional, Coordinating PI, Chief Investigator on academic clinical trial receiving drug and funding: Sosei Heptares. All other authors have declared no conflicts of interest.