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

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.

• Authors: Mark Rosenthal, Richard Curry, David A Reardon, Erik Rasmussen, Vijay V Upreti, Michael A Damore, Haby A Henary, John S Hill, Timothy Cloughesy
• Journal: Cancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 84 Issue 2 Pg. 327-336 (08 2019) ISSN: 1432-0843 [Electronic] Germany
• PMID: 31154523 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• AMG 595
• Immunoconjugates
• Maytansine

Topics

• Adult
• Aged
• Brain Neoplasms (drug therapy, pathology)
• Female
• Glioma (drug therapy, pathology)
• Humans
• Immunoconjugates (pharmacokinetics, therapeutic use)
• Male
• Maytansine (analogs & derivatives, pharmacokinetics, therapeutic use)
• Middle Aged
• Treatment Outcome