Abstract 688P
Background
HMBD-001 is an IgG1 humanised monoclonal antibody that directly blocks the dimerisation of HER3 to HER2 and EGFR. The ongoing first-in-human trial is an open-label, multi-centre, phase I/IIa adaptive study design (CRUKD/22/002) of HMBD-001 in patients with tumour types known to overexpress HER3. We report the pharmacokinetic profile of HMBD-001 from the initial dose escalation cohorts.
Methods
Patients (n = 17) were allocated to dose-escalating cohorts and administered an IV once weekly infusion dose (150, 300, 600, 1200, 1800 and 3000 mg) over 2 hours. The pharmacokinetics of HMBD-001 were evaluated over 7 days following administration on days 1 and 15 of cycle one. Concentrations of HMBD-001 in serum samples were determined by a validated bridging enzyme-linked immunosorbent assay (ELISA) method with a lower limit of quantification of 250 ng/mL. Pharmacokinetic parameters, including maximum concentration (Cmax), Tmax, area under curve (AUC), terminal half-life (t1/2), and clearance (CL), were calculated by non-compartmental analysis using Certara WinNonlin software (version 8.3). A population pharmacokinetic approach was explored using Lixsoft Monolix Suite (version 2023R1).
Results
HMBD-001 Cmax and AUC values increased linearly with dose on days 1 and 15 of treatment and a T1/2 of 12.2 +/- 3.4 days was calculated at a dose of 3000mg. Drug clearance values observed on day 15 (dose 3) were significantly lower than those on day 1 (dose 1) (p = 0.017). Preliminary population pharmacokinetic suggest that the data are best described by a one compartmental model, with sex and weight as covariates for clearance and volume of distribution, respectively.
Table: 688P
Pharmacokinetics of HMBD-001 on day 1 of dosing
| Cohort | n | Dose (mg) | Cmax (μg/mL) | Tmax (h) | Ctrough (μg/mL) | CL (mL/h) | AUC (μg/mL.h) | T1/2 (days) |
| 1 | 1 | 150 | 33 | 2.7 | 11 | 33.3 | 4499 | 4.5 |
| 2 | 1 | 300 | 98.3 | 2.1 | 25.6 | 25.4 | 11822 | 5.8 |
| 3 | 3 | 600 | 137.0 ± 34.9 | 4.1 - 25.1 | 62.7 ± 17.7 | 21.8 ± 6.4 | 29251 ± 9062 | 6.4 ± 0.6 |
| 4 | 3 | 1200 | 296.2 ± 60.2 | 2.2 - 7.4 | 148.4 ± 6.4 | 15.6 ± 1.6 | 77099 ± 7548 | 8.6 ± 2.2 |
| 5 | 6 | 1800 | 412.1 ± 57.8 | 2.4 - 4.9 | 158.6 ± 41.2 | 23.7 ± 5.0 | 79966 ± 23210 | 6.5 ± 1.6 |
| 6 | 3 | 3000 | 841.2 ± 209.3 | 2.2 - 2.8 | 368.3 ± 92.4 | 13.4 ± 1.9 | 227419 ± 32461 | 12.2 ± 3.4 |
Conclusions
The pharmacokinetic data generated to date are consistent with dose-dependent increases in drug exposure for HMBD-001. A T1/2 of approximately 12 days is predicted.
Clinical trial identification
NCT05057013.
Editorial acknowledgement
Legal entity responsible for the study
Cancer Research UK.
Funding
Cancer Research UK, Centre for Drug Development.
Disclosure
All authors have declared no conflicts of interest.
Resources from the same session
710P - A retrospective study on the safety and adequacy of fresh biopsies for next generation sequencing in early-phase clinical trials
Presenter: Edoardo Crimini
Session: Poster session 17
711TiP - A phase I/II, first-in-human, open-label, dose-escalation study of TAK-186, an EGFR × CD3ε COBRA T cell engager, in adult patients with unresectable, locally advanced, or metastatic solid tumors
Presenter: Andrew Weickhardt
Session: Poster session 17
712TiP - A phase I/II multicenter, open-label, dose-escalation, safety, pharmacodynamic, and pharmacokinetic study of Q901 administered via intravenous infusion in adult patients with selected advanced solid tumors with a cohort expansion at the recommended phase II dose
Presenter: Angela Alistar
Session: Poster session 17
713TiP - A phase I study of PRT3789, a potent and selective degrader of SMARCA2 in patients with advanced or metastatic solid tumors and a SMARCA4 mutation
Presenter: Ibiayi Dagogo-Jack
Session: Poster session 17
714TiP - A phase Ia/Ib, first-in-human, dose-escalation study evaluating the safety, tolerability, and efficacy of IOS-1002, a LILRB1, LILRB2, and KIR3DL1 targeting HLA-derived fusion protein administered alone or in combination with a PD-1 antibody in patients with advanced solid tumors
Presenter: Stephen Luen
Session: Poster session 17
715TiP - ARTS-021-1001: Phase I/II study of ARTS-021, a potent, oral administrated, selective CDK2 inhibitor, in advanced or metastatic solid tumors
Presenter: Yan Wang
Session: Poster session 17
716TiP - DETERMINE: A pioneering UK precision medicine trial for rare cancers
Presenter: Gary Middleton
Session: Poster session 17
717TiP - An open-label, multicentre, dose-escalation, first-in-human phase I study to evaluate safety, tolerability and antineoplastic activity of OATD-02 (dual arginase 1 and arginase 2 inhibitor) in patients with selected advanced and/or metastatic solid tumors
Presenter: Marta Dudek
Session: Poster session 17
718TiP - DEKA-1 a dose-finding phase I trial: Observing safety and biomarkers using DK210 (EGFR) for inoperable locally advanced and/or metastatic EGFR+ tumors with progressive disease failing systemic therapy
Presenter: Elizabeth Moser
Session: Poster session 17
719TiP - A phase I/Ib study of the Werner (WRN) helicase inhibitor HRO761 as single agent and in combination with irinotecan or tislelizumab in patients with microsatellite instability-high (MSIhi) or mismatch repair deficient (dMMR) advanced solid tumors
Presenter: Michele Moschetta
Session: Poster session 17