Abstract 493TiP
Background
Human epidermal growth factor receptor (HER)3 is a member of the HER family of transmembrane proteins. HER3 lacks kinase activity and must be transactivated by dimerisation with a kinase-active partner for signal transduction. In ligand-dependent activation, the NRG1 ligand can stabilise HER3 in the open conformation. However, ligand-independent heterodimerization can also occur. Overexpression of HER3 is observed in multiple tumour types and associated with poor clinical outcome. HMBD-001 is an IgG1 humanized monoclonal antibody specifically targeting HER3 with a novel mechanism of action. It directly binds to and blocks the heterodimerization interface of HER3 and has the potential to inhibit both ligand dependent and independent activation of HER3.
Trial design
HMBD-001 is being evaluated in a first in human, multi-centre, open-label, non-randomised phase I/IIa trial comprised of an initial dose-escalation phase (Part A) in advanced solid tumours resistant/refractory to conventional treatment known to overexpress HER3 or with NRG1 fusions, followed by a dose-expansion phase (Part B) in combination with other agents in metastatic castration-resistant prostate cancer and other solid tumours (NCT05057013). Part A of the trial consists of an initial intra-patient dose escalation stage, followed by an inter-patient dose escalation stage utilising a one-stage Bayesian continuous reassessment method design. The trial began enrolling in October 2021 and is ongoing in the UK. Cohort 1 and 2 have been completed and cohort 3 currently active. The primary objectives are to determine the safety and tolerability and the recommended dose and schedule for phase II evaluation (RP2D). The pharmacokinetic profile, clinical and pharmacodynamic activity of HMBD-001 as a single agent in biomarker-defined cohortswill be evaluated. Patients in Part A will have archival tumour tissue retrospectively analysed. In Part B pre- and on-treatment tumour biopsies will be collected. Potential predictive and pharmacodynamic biomarkers including pHER3, pERK and Ki67 will be evaluated alongside circulating tumour biomarkers.
Clinical trial identification
ClinicalTrials.gov Identifier: NCT05057013.
Editorial acknowledgement
Legal entity responsible for the study
Cancer Research UK.
Funding
Cancer Research UK.
Disclosure
J.S. de Bono: Financial Interests, Personal, Advisory Board: Amgen, Astellas, AstraZeneca, Bayer, Bioxcel Therapeutics, Boehringer Ingelheim, Cellcentric, Daiichi, Eisai, Genentech Roche, Genmab, GlaxoSmithKline, Janssen, Merck Serono, Merck Sharp & Dohme, Orion Pharma, Pfizer, Qiagen, Sanofi Aventis, Sierra Oncology, Taiho, Terumo, Vertex Pharmaceuticals; Financial Interests, Institutional, Advisory Board: Harpoon; Financial Interests, Institutional, Research Grant: Astellas, AstraZeneca, Bayer, Cellcentric, Daiichi, Genentech Roche, Genmab, GlaxoSmithKline, Harpoon, Janssen, Merck Serono, Merck Sharp & Dohme, Orion Pharma, Pfizer, Sanofi Aventis, Sierra Oncology, Taiho, Vertex Pharmaceuticals, Crescendo Biologics; Non-Financial Interests, Principal Investigator: Amgen, Astellas, AstraZeneca, Bayer, Bioxcel Therapeutics, Boehringer Ingelheim, Cellcentric, Daiichi, Eisai, Genentech Roche, Genmab, GlaxoSmithKline, Harpoon, Janssen, Menarini Silicon Biosystems, Merck Serono, Merck Sharp & Dohme, Orion Pharma, Pfizer, Qiagen, Sanofi Aventis, Sierra Oncology, Taiho, Terumo, Vertex Pharmaceuticals; Non-Financial Interests, Institutional, Product Samples: Daiichi, Bayer, Pfizer, Merck Serono, AstraZeneca, Harpoon, Sierra Oncology, Genentech/Roche, Sanofi Aventis, GlaxoSmithKline. S. Lord: Financial Interests, Personal, Advisory Board: Sanofi, Rejuversen; Financial Interests, Personal, Invited Speaker: Sanofi, Prosigna, Eisai, Roche, Pfizer, Novartis; Financial Interests, Personal, Ownership Interest, Co-founder of company: Mitox Therapeutics; Financial Interests, Institutional, Invited Speaker: Boehringer Ingelheim, Piqur Therapeutics, AstraZeneca, Carrick Therapeutics, Sanofi, Merck KGaA, Synthon, Roche, BioInvent International, RS Oncology; Financial Interests, Institutional, Research Grant: Pathios Therapeutics; Non-Financial Interests, Advisory Role: Carrick Therapeutics. E.K. Rowinsky: Financial Interests, Personal and Institutional, Full or part-time Employment: Hummingbird Bioscience. N.A. Gandhi: Financial Interests, Institutional, Full or part-time Employment, I am an employee at Hummingbird Bioscience: Hummingbird Bioscience; Financial Interests, Institutional, Stocks/Shares, I am a shareholder at Hummingbird Bioscience: Hummingbird Bioscience. D. Thakkar: Financial Interests, Institutional, Full or part-time Employment: Hummingbird Bioscience. P.J. Ingram: Financial Interests, Institutional, Full or part-time Employment, CEO of Hummingbird Bioscience: Hummingbird Bioscience; Financial Interests, Institutional, Stocks/Shares: Hummingbird Bioscience; Financial Interests, Institutional, Other, IP Ownership interests from a discovery or technology relating to health or medicine: Hummingbird Bioscience. N. Padmanabhan: Financial Interests, Institutional, Full or part-time Employment: Hummingbird Bioscience. P. Neal: Financial Interests, Institutional, Full or part-time Employment: Cancer Research UK. H.S. Walter: Financial Interests, Personal, Advisory Board: Merck; Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Institutional, Research Grant: Gilead. J.D. Boyd-Kirkup: Financial Interests, Personal, Full or part-time Employment: Hummingbird Bioscience; Financial Interests, Personal, Stocks/Shares: Hummingbird Bioscience. All other authors have declared no conflicts of interest.