A phase 1 study evaluating ABT-414 in combination with temozolomide (TMZ) for subjects with recurrent or unresectable glioblastoma (GBM).
Central Nervous System Tumors
Central Nervous System Tumors
2014 ASCO Annual Meeting
J Clin Oncol 32:5s, 2014 (suppl; abstr 2021)
2014 ASCO Annual Meeting!
Session: Central Nervous System Tumors
Type: Poster Highlights Session
Time 1: Friday May 30, 1:00 PM to 4:00 PM
Location 1: E354b
Time 2: Friday May 30, 4:30 PM to 5:45 PM
Location 2: E450
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Author(s): Hui Kong Gan, Lisa Fichtel, Andrew B. Lassman, Ryan Merrell, Martin J. Van Den Bent, Priya Kumthekar, Andrew Mark Scott, Michelle Pedersen, Erica Gomez, JuDee Fischer, William Ames, Hao Xiong, Matthew W. Dudley, Wijith Munasinghe, Lisa Roberts-Rapp, Peter Ansell, Kyle D. Holen, David A. Reardon; Austin Health and Ludwig Institute for Cancer Research, Melbourne, Australia; South Texas Oncology and Hematology, San Antonio, TX; Columbia University Medical Center, New York, NY; Northshore University Health System, Evanston, IL; Erasmus MC Cancer Center, Rotterdam, Netherlands; Northwestern University Health System, Chicago, IL; AbbVie, Inc., North Chicago, IL; Dana-Farber Cancer Institute, Boston, MA
Background: Patients (pts) with recurrent GBM have few treatment options and a very poor prognosis. GBM tumors often exhibit aberrant epidermal growth factor receptor (EGFR) proliferative signaling. ABT-414 is an antibody drug conjugate consisting of a unique antibody targeting active EGFR or mutant EGFRvIII linked to a potent, toxic anti-microtubule agent monomethylauristatin F (MMAF). ABT-414 has demonstrated high antitumor activity in preclinical GBM tumor models harboring either wild type EGFR or EGFRvIII. Methods: Objectives were to evaluate the toxicities, pharmacokinetics (PK), and the recommended phase 2 dose of ABT-414 when administered every other week (QOW) in combination with TMZ in pts with recurrent or unresectable GBM. Assessments include adverse events (AEs, NCI-CTCAE), PK parameters, objective response (RANO criteria) and tumor tissue EGFR biomarkers. Results: As of Jan 1, 2014, safety data was compiled for 12 pts (6/6, Male/Female, median age 48). Common (≥ 3 pts) adverse events include blurred vision (n=5), corneal deposits (n=4), foreign body sensation in the eye, nausea, pyrexia, and headache (n=3 each). Grade 3/4 AEs include lymphopenia, corneal deposits, skin infection, and blood cholesterol increase (n=1 each). Three cohorts have been treated to date (0.5, 1.0, 1.5 mg/kg). One dose limiting toxicity of grade 3 corneal deposits was reported at 1.0 mg/kg with improvement of symptoms after a dose reduction. ABT-414 PK results in 7 pts appeared to be dose proportional from 0.5-1.0 mg/kg, with mild accumulation using QOW dosing, and a half-life of 7-8 days. As of Jan 9, best responses for 9 pts with measurable disease at baseline include 1 complete response (CR) and 2 partial responses (33%). Patient samples are being evaluated for EGFR amplification, EGFR VIII status and expression of EGFR mRNA to determine which marker best associates with clinical response. Conclusions: Preliminary safety data demonstrate a unique toxicity pattern related to MMAF-induced corneal epithelial microcysts. Preliminary responses in 3/9 pts with TMZ refractory GBM, including 1 CR, warrant further study. Phase 2 studies with ABT-414 in GBM are being planned. Clinical trial information: NCT01800695.
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