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
720TiP - Phase I, open-label, first-in-human (FIH) study of JZP815 in advanced or metastatic solid tumors harboring mitogen-activated protein kinase (MAPK) alterations
Presenter: Abdul-Rafeh Naqash
Session: Poster session 17
722TiP - CLAUDIO-01: A multicentric phase I/II trial to evaluate the safety and efficacy of SOT102 as monotherapy and in combination with standard of care (SoC) in patients with gastric, gastroesophageal junction(GEJ), and pancreatic adenocarcinoma
Presenter: Radka Obermannova
Session: Poster session 17
732P - Efficacy and safety of high-dose chemotherapy as second or subsequent salvage therapy in relapsed or refractory germ cell cancer patients: A multicentric analysis
Presenter: Christoph Seidel
Session: Poster session 17
733P - Testicular cancer: Trends in incidence and demographics from 23,214 cases in California from 2000-2020
Presenter: David Benjamin
Session: Poster session 17
734P - Primary retroperitoneal germ-cell tumours (pR-GCT): Evaluation of treatment outcomes of an international collaboration (PRIMERE study-IGG05)
Presenter: Patrizia Giannatempo
Session: Poster session 17