Abstract 2506: A phase 1 study of ABT-806, a humanized recombinant anti-EGFR monoclonal antibody, in patients with advanced solid tumors
Authors: Cleary James M. , Yee Lorrin Kwock-Chong , Azad Nilofer , Carducci Michael , Cosgrove David , Limaye Sewanti , Gandhi Leena , Pedersen Michelle , Ansell Peter , Ames William , Sharma Shringi , Hsu Ya-Hui , Munasinghe Wijith , Reilly Edward , Holen Kyle D. , Humerickhouse Rod 
Published: August 2012

Abstract
Background: ABT-806 is a humanized recombinant IgG1α monoclonal antibody that binds to a unique EGFR epitope exposed only in the EGFRde2-7 (EGFRvIII) deletion mutant and activated EGFR proteins. Preclinical data suggest that ABT-806 does not significantly bind to non-activated, wild-type EGFR expressed on normal tissues. This phase I study evaluates the safety, pharmacokinetic (PK) profile, and antitumor activity of ABT-806 in patients (pts) with advanced solid tumors and suggests a recommended phase 2 dose (RPTD). Methods: Pts with advanced solid tumors thought to be EGFR expressing, adequate organ function and ECOG performance status were eligible for enrollment. Glioblastoma pts were not eligible for the dose escalation phase. Pts received ABT-806 intravenously at a rate no higher than 15 mg/min. Doses explored were 2, 6, 12, 18, and 24 mg/kg every other week, preceded by 30 min with acetaminophen 650 mg and diphenhydramine 25Δ50 mg. A 3+3 dose escalation design was followed. Assessments included adverse events (AEs) graded by NCI CTCAE v4.0, PK, maximum tolerated dose (MTD), RPTD, and tumor response by RECIST. Results: At the time of reporting, 26 pts (M/F, 14/12; median age, 63 y; range, 39α81 y) have been dosed. No dose limiting toxicities (DLTs) were observed at the 2, 6, 12, and 18 mg/kg dose levels. One pt in the 24 mg/kg group experienced a DLT of a grade 3 morbilliform rash, resolving after the administration of loratidine. Other ABT-806αrelated grade 3/4 AEs were dyspnea (15%) and hypotension (12%). Frequently occurring AEs (≥10%) possibly or probably related to ABT-806 were nausea (23%), vomiting (19%), fatigue (15%), and rash (12%). The systemic exposures (AUC and Cmax) to ABT-806 were dose-proportional between 2α24 mg/kg and the terminal half-life (mean t1/2) was ∼9 days. Sixteen pts had at least 1 post-baseline tumor assessment. Five pts achieved stable disease (more than 8 weeks) as best response (head and neck cancer, 2; colorectal cancer, 2; lung cancer, 1). One pt with EGFR amplified head and neck cancer at 6 mg/kg dose had stable disease for 23 weeks. The RPTD was determined as the highest protocol-defined dose tested at 24 mg/kg, as the MTD was not reached. Infrequent episodes of rash were observed, 5 pts with grade 1/2 and only 1 pt with grade 3. Three pts reported grade 1 diarrhea. EGFR H-score has been performed for each pt enrolled and will be correlated with clinical outcome. EGFRde2-7 analysis is in process. Conclusions: ABT-806 showed a unique PK and safety profile distinct from other anti-EGFR therapies. The PK appeared to be linear across doses. The RPTD was the highest dose tested (24 mg/kg). Unlike other EGFR inhibitors, rash was infrequent and typically grade 1 or 2. The exception was 1 grade 3 morbilliform rash that had a very different morphology than the typical acneiform rash associated with EGFR inhibitors. Phase 2 development in the EGFR amplified and/or EGFRde2-7 pts is planned.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2506. doi:1538-7445.AM2012-2506