Abstract B149: Clinical pharmacokinetics (PK) of an anti-epidermal growth factor receptor (EGFR) antibody drug conjugate (ADC), ABT-414, in patients with glioblastoma multiforme (GBM) or advanced solid tumors likely to overexpress EGFR: Results from phase 1 studies
Authors: Mittapalli Rajendar K. , Munasinghe Wijith P. , Myasein Zaw-Myo-Htet F. , Hoffmann David M. , Lai Rose K. , Holen Kyle D. , Xiong Hao 
Published: May 2016

Abstract
Introduction: ABT-414 is an ADC consisting of an anti-EGFR monoclonal antibody ABT-806 conjugated to a potent microtubule toxin monomethylauristatin F (MMAF) via a non-cleavable maleimidocaproyl (mc) linker. The antibody component of ABT-414 delivers MMAF to antigen-positive cells, where it disrupts microtubule network and induces cell cycle arrest and apoptosis. ABT-414 is currently in phase 2 clinical trials evaluating its efficacy in GBM subjects with EGFR amplification. Here we present the PK results from phase 1 studies.
Methods: Two ongoing phase 1 studies are examining the safety, PK, and efficacy of ABT-414 in patients with GBM and solid tumors. Three analytes, including, ABT-414, total ABT-806, cys-mcMMAF, were measured to characterize ABT-414 PK. In GBM subjects, ABT-414 was administered Q2W in 3 arms: 1. in combination with radiation plus temozolomide (TMZ); 2. in combination with TMZ; 3. As monotherapy. In subjects with advanced solid tumors, ABT-414 monotherapy was administered as either a Q3W or as a weekly (2 week on/1 week off) IV dosing. An electrochemiluminescence immunoassay was used to determine ABT-414 and total ABT-806 concentrations and an LCMS/MS assay was used to measure cys-mcMMAF concentrations. PK parameters were computed using non compartmental analysis. Immunogenicity was assessed by measuring anti-drug antibody (ADA) against ABT-414.
Results: The maximum concentrations (Cmax) of ABT-414 and total ABT-806 are typically achieved following the end of infusion and the exposures are approximately dose proportional in both studies. The harmonic mean t1/2 of ABT-414, total ABT-806, and cys-mcMMAF in days (%CV) were 7.2 (32.6), 9.4 (40.8), 4.3 (33.2), respectively. The mean clearance (%CV) of ABT-414 is 0.176 (23.3) and 0.267 (49.6) mL/hr/kg in GBM and solid tumor subjects, respectively. The systemic cys-mcMMAF exposures are ∼500-fold lower than ABT-414 on molar basis. The PK of ABT-414 at 1.25 mg/kg is not affected by temozolomide in recurrent GBM subjects [ABT-414 AUC (mg*hr/mL): with TMZ: 9.14 ± 2.75 without TMZ: 10.4 ± 1.98]. The exposures of cys-mcMMAF are comparable between subjects with normal renal function and subjects with mild or moderate renal impairment [cys-mcMMAF Cmax (ng/ml/mg/kg): Normal: 0.217 (0.189 - 0.249); mild: 0.199 (0.166 - 0.240); moderate: 0.168 (0.09 - 0.313)]. No correlation between ABT-414 exposures and creatinine clearance was observed. The exposures of ABT-414 and cys-mcMMAF are comparable between subjects with or without EGFR amplification [ABT-414 AUC (mg*hr/mL/mg/kg): EGFR (+): 5.3 ± 1.8; EGFR (-): 4.2 ± 1.0; Cys-mcMMAF AUC (ng*hr/mL/mg/kg): EGFR (+): 32.4 ± 20.8; EGFR (-): 28.8 ± 12.8]. Of 152 patients treated with ABT-414 and evaluable for ADA, 5.3% and 2.6% tested ADA positive at baseline and post-treatment, respectively.
Conclusions: ABT-414 showed linear PK in the ongoing phase 1 studies in the dose ranges studied. Systemic exposures of cys-mcMMAF are significantly lower than ABT-414. Temozolomide appears to have no effect on ABT-414 PK or vice versa. EGFR amplification, mild or moderate renal impairment appear to have little effect on the PK of ABT-414 or cys-mcMMAF. Available data show lack of immunogenicity to ABT-414 treatment.
Citation Format: Rajendar K. Mittapalli, Wijith P. Munasinghe, Zaw-Myo-Htet F. Myasein, David M. Hoffmann, Rose K. Lai, Kyle D. Holen, Hao Xiong. Clinical pharmacokinetics (PK) of an anti-epidermal growth factor receptor (EGFR) antibody drug conjugate (ADC), ABT-414, in patients with glioblastoma multiforme (GBM) or advanced solid tumors likely to overexpress EGFR: Results from phase 1 studies. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B149.