A CRUK phase I/IIA, first in human dose-escalation and expansion trial of HMBD-001 (an anti-HER-3 antibody) in patients with advanced HER3-positive solid tumours

Human epidermal growth factor receptor (HER)3 is a HER family transmembrane protein. Overexpression of HER3 is observed in multiple solid tumour types and are associated with poor clinical outcome. HMBD-001 is an IgG1 humanized monoclonal antibody specifically targeting HER3 with a unique mechanism of action, inhibiting both ligand-dependent and independent activation. HMBD-001 is being evaluated in a first in human, multi-centre, open-label, non-randomised phase 1/IIA trial: Part A dose-escalation, with an initial intra-patient dose escalation, followed by inter-patient dose escalation utilising a one-stage Bayesian continuous reassessment design in advanced solid tumours commonly overexpressing HER3; and Part B, a dose-expansion phase in combination in metastatic castration-resistant prostate cancer (mCRPC) (NCT05057013). The primary objectives of Part A are to determine safety and tolerability and the recommended dose and schedule for phase 2 evaluation (RP2D). The pharmacokinetic profile, clinical and pharmacodynamic activity of HMBD-001 as a single agent and potential predictive and pharmacodynamic biomarkers are being evaluated. As of 11 April 2023, 17 patients with advanced solid tumours have received weekly infusions of HMBD-001 monotherapy across 6 cohorts (150mg-3000mg). In total, 70 HMBD-001 treatment related adverse events (TRAEs) have been reported. 14 (82.4%) patients have had ≥1 TRAE. No grade ≥3 TRAEs nor DLTs have been observed. More TRAEs have been observed at higher doses. Gastrointestinal disorder TRAEs are the most frequently reported (45.7%, 32/70); 13 patients (76.5%) experienced grade ≤ 2 diarrhoea. 4 patients (23.6%) have experienced trial-specific events of special interest; grade ≤2 infusion related reactions. Stable disease has been recorded in 4/12 evaluable heavily pre-treated patients. Preliminary data supports a highly tolerable safety profile, supporting combination therapy. HMBD-001 will next be evaluated in Part B in biomarker selected mCRPC with Enzalutamide. Trials of HMBD-001 in squamous NSCLC and NRG1 fusions are also planned for Q3/4 2023.