Abstract 870: A clinical study of ABT-806, a humanized recombinant anti-EGFR monoclonal antibody, in patients with recurrent glioblastoma multiforme.
Authors: Reardon David A. , Cleary James M. , Xiong Hao , Munasinghe Wijith P. , Hsu Ya-Hui , Reilly Edward B. , Qian Jiang , Pedersen Michelle S. , Humerickhouse Rod A. , Holen Kyle D. 
Published: August 2014

Abstract
Background: Glioblastoma (GBM), the most common primary CNS malignancy, has a dismal prognosis with a median survival of under 15 months. Epidermal growth factor receptor (EGFR) is commonly amplified, overexpressed, and mutated in GBM and has been implicated in tumor growth and resistance to therapy. ABT-806 is a humanized recombinant IgG1k monoclonal antibody that binds to a unique EGFR epitope exposed only in the untethered, (activated) state of EGFR or when the de2-7 (EGFRvIII) deletion mutation is present. ABT-806 has shown significant antitumor activity over other EGFR antibodies in both in vitro and in vivo models of GBM. We evaluated the safety, pharmacokinetics (PK), and antitumor activity of ABT-806 in a cohort of recurrent GBM patients treated at the recommended phase 2 dose determined from the dose-escalation portion of this phase 1 study.
Methods: Patients with recurrent, EGFR-amplified GBM and measurable disease by RECIST (v1.1) were included. ABT-806 was administered at 24 mg/kg intravenously every other week until disease progression or study withdrawal. Tumor response by MRI or CT was assessed every 8 weeks. Adverse events (AEs) were graded by NCI CTCAE v4.0. Serum samples for determination of ABT-806 concentration and antidrug antibody were collected at multiple time points throughout the study. Archival tumor analysis for EGFR amplification/mutation was also performed.
Results: Among 11 patients; median age was 60 years (range 39 to 69) and 9 were male. Median number of prior therapies was 2 (range 1 to 7). Six patients had prior bevacizumab exposure. No patients required dose modification. Hypophosphatemia was the only treatment-related emergent AE that occurred in 2 or more patients. Best responses were n=3 stable disease, n=7 progressive disease. One patient withdrew consent prior to the first post-baseline tumor assessment. Median time to disease progression and median progression free survival [95% CI] were 43 [22,57] and 29 [25,57] days, respectively. PK and EGFRde2-7 data were not available at the time of abstract submission.
Conclusions: While ABT-806 related AEs were infrequent, there was little evidence of a clinical benefit in this refractory GBM population. Whether the lack of significant anti-tumor effect was due to poor binding to intracranial tumors, lack of response to the mechanism of action, or the refractory population is to be determined. A study is ongoing to evaluate the biodistribution of 111Indium-labeled ABT-806 in pts with advanced solid tumor types, including GBM. Further preclinical efforts to increase the potency of ABT-806 are also ongoing.
Citation Format: David A. Reardon, James M. Cleary, Hao Xiong, Wijith P. Munasinghe, Ya-Hui Hsu, Edward B. Reilly, Jiang Qian, Michelle S. Pedersen, Rod A. Humerickhouse, Kyle D. Holen. A clinical study of ABT-806, a humanized recombinant anti-EGFR monoclonal antibody, in patients with recurrent glioblastoma multiforme. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 870. doi:10.1158/1538-7445.AM2013-870