A phase 1 study of ABT-806 in subjects with advanced solid tumors

Purpose: ABTa-806, a humanized recombinant monoclonal antibody, binds a unique epidermal growth factor receptor (EGFR) epitope exposed in the EGFRde2-7 (EGFRvIII) deletion mutant and other EGFR proteins in the activated state. This phase I study evaluated the safety, pharmacokinetics, and recommended phase two dose (RP2D) of ABT-806 in patients with solid tumors that commonly overexpress activated EGFR or EGFRvlll. Methods: Patients with advanced solid tumors, including glioblastoma, were eligible. Following a dose escalation phase, expanded safety cohorts of patients with solid tumors or EGFR-amplified glioblastoma were enrolled. Adverse events (AEs) were graded by National Cancer Institute Common Terminology Criteria for Adverse Events v4.0; tumor response was assessed by Response Evaluation Criteria in Solid Tumors v1.1. EGFR protein expression was quantified by immunohistochemistry. Results: 49 patients were treated. Frequent AEs (≥10 %) possibly/probably related to ABT-806 were fatigue (18 %), nausea (16 %), dermatitis acneiform (12 %), and vomiting (10 %). Only one dose-limiting toxicity (grade three morbilliform rash) occurred. The RP2D was the pre-specified highest dose (24 mg/kg). Systemic exposures were dose proportional between 2 and 24 mg/kg. Median time to progression was 55 days (95 % confidence interval, 53-57) in all patients and 43 days (22-57) for glioblastoma patients. No objective responses occurred; however, two patients had prolonged stable disease. An EGFR-amplified penile cancer patient has stable disease lasting over 2.5 years. Conclusions: ABT-806 has unique pharmacokinetic and safety profiles. Toxicities were infrequent and typically low grade at the RP2D. Linear ABT-806 pharmacokinetics suggest lack of significant binding to wild-type EGFR in normal tissues.