HER2 is dysregulated in a wide range of solid tumors, including breast cancer, and is an attractive target for tailored oncologic treatment. GBR 1302 is a HER2xCD3 bispecific antibody that redirects cytotoxic T-cells to kill HER2 overexpressing cancer cells. This unique mode of action is anticipated to result in superior antitumor activity in HER2-positive tumors by harnessing the cytotoxic capabilities of patients’ existing T-cells.
This ongoing, phase 1, first-in-human, open-label, multicenter, dose-escalation study is evaluating GBR 1302 in adults with progressive HER2-positive solid tumors for which no standard or curative treatment is available. Subjects receive intravenous GBR 1302 on Day 1 and Day 15 in 28-day treatment cycles at escalating dose levels, starting at 1 ng/kg. The first 4 cohorts consisted of a single subject; subsequent cohorts are being enrolled using a 3 + 3 design. Blood samples were collected for pharmacokinetic (PK) and anti-drug antibody (ADA) analyses (secondary endpoints). Quantification of GBR 1302 serum concentrations (for PK) and detection/confirmation of anti GBR 1302 antibodies (for immunogenicity) were performed using validated LC/MS/MS and ELISA methods, respectively. PK parameters were evaluated using standard non-compartmental methods.
As of 21 August 2018, PK data were available from 31 subjects over dose range of 1 ng/kg to 750 ng/kg. Serum concentrations were less than the lower limit of quantification of 50 pg/mL at the first dose (1 ng/kg), and only transient concentrations were observed at 3 and 10 ng/kg dose levels. Evaluable PK profiles were observed from 30 ng/kg onwards. GBR 1302 showed maximum serum concentration (Cmax) around the end of infusion, after which serum concentrations declined bi-exponentially with a mean terminal half-life of around 4 to 7 days. Both Cmax and area under the curve (AUC0-t) showed a near dose-proportional increase up to 750 ng/kg (maximum evaluated dose). None of the samples collected from subjects up to cohort 5 showed positive ADA response.
Per ongoing analysis, GBR 1302 showed a favorable, linear PK. None of the subjects evaluated so far showed positive ADA response.
Editorial assistance was provided by Jacqueline Benjamin, PhD of Prescott Medical Communications Group, Chicago, IL.
NCT02829372.
Glenmark Pharmaceuticals SA.
Glenmark Pharmaceuticals SA.
G. Gudi, E. Fluhler: Employee of Glenmark Pharmaceuticals Inc., V. Ca, S. Gn: Employee of Glenmark Pharmaceuticals, Ltd., C. von Gunten, J. Back: Employee of Glenmark Pharmaceuticals SA.