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Clinical Trial
. 2019 Aug;84(2):327-336.
doi: 10.1007/s00280-019-03879-2. Epub 2019 Jun 1.

Safety, tolerability, and pharmacokinetics of anti-EGFRvIII antibody-drug conjugate AMG 595 in patients with recurrent malignant glioma expressing EGFRvIII

Mark Rosenthal  1 , Richard Curry  2 , David A Reardon  3 , Erik Rasmussen  4 , Vijay V Upreti  5 , Michael A Damore  4 , Haby A Henary  4 , John S Hill  6 , Timothy Cloughesy  7
Affiliations
Clinical Trial

Safety, tolerability, and pharmacokinetics of anti-EGFRvIII antibody-drug conjugate AMG 595 in patients with recurrent malignant glioma expressing EGFRvIII

Mark Rosenthal et al. Cancer Chemother Pharmacol. 2019 Aug.

Abstract

Purpose: Epidermal growth factor receptor variant III (EGFRvIII) is expressed in a significant percentage of primary and recurrent glioblastoma (GBM), a common malignant primary brain tumor in adults. AMG 595 is an antibody-drug conjugate comprising a fully human, anti-EGFRvIII monoclonal antibody linked to DM1. The study goals were to assess safety, tolerability, and pharmacokinetics of AMG 595 in GBM.

Methods: In this phase 1, first-in-human, open-label, sequential-dose, exploration study, adults with recurrent GBM received AMG 595 once every 3 weeks (Q3W) according to incremental dosing cohorts (0.5-3.0 mg/kg). Primary endpoints were to assess safety, the incidence of dose-limiting toxicities (DLTs), objective response (per Macdonald criteria), evaluate pharmacokinetics, and estimate the maximum tolerated dose (MTD).

Results: Of 382 patients screened, 32 were enrolled and received ≥ 1 dose of AMG 595. Ten patients experienced 18 DLTs (all grade 4 thrombocytopenia), and the MTD was 2.0 mg/kg. Twenty-eight patients (88%) experienced ≥ 1 treatment-related adverse event (AE); the most common AEs were thrombocytopenia (50%) and fatigue (25%). Grade ≥ 3 treatment-related AEs occurred in 17 patients (53%); 11 (34%) had serious treatment-emergent AEs, and none were considered treatment related. Pharmacokinetic profiles indicated low levels of circulating unconjugated antibody and cytotoxin, dose-proportional increases in plasma exposures for the conjugated antibody over the studied range, and less than twofold accumulation following multiple Q3W dosing. Two patients (6%) had partial responses; 15 (47%) had stable disease.

Conclusions: AMG 595 exhibited favorable pharmacokinetics and is a unique therapy with possible benefit for some patients with EGFRvIII-mutated GBM with limited therapeutic options.

Keywords: AMG 595; Antibody–drug conjugate; DM1; EGFRvIII; Glioblastoma.

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