ESMO Congress 2023 | OncologyPRO

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 (C_max), T_max, area under curve (AUC), terminal half-life (t_1/2), 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 C_max and AUC values increased linearly with dose on days 1 and 15 of treatment and a T_1/2 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)	C_max (μg/mL)	T_max (h)	C_trough (μg/mL)	CL (mL/h)	AUC (μg/mL.h)	T_1/2 (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 T_1/2 of approximately 12 days is predicted.