Atnt-01abt-414 Mono- or Combination Therapy With Temozolomide (tmz) Rechallenge in Patients With Recurrent Glioblastoma (gbm) and Amplified Epidermal Growth Factor Receptor (egfr): a Phase I Study
Year: 2015
Type: article
Study design: Clinical Trial
Abstract: BACKGROUND: Aberrant EGFR signaling plays a vital role in GBM oncogenesis. ABT-414 is an antibody-drug conjugate with a toxic payload (monomethylauristatin F) linked to ABT-806, an antibody targeted to activated EGFR. This phase I, open-label, 3-arm study (NCT01800695) evaluates ABT-414 mono- or combination therapy with TMZ rechallenge in patients with GBM. Herein, we report outcomes in recurrent GBM. METHODS: Eligible patients (≥18 years) had recurrent supratentorial GBM and Karnofsky performance status ≥70. ABT-414 was given intravenously every 2 weeks with TMZ rechallenge (150-200 mg/m2 days 1-5 q28; Arm B) or as monotherapy (Arm C). ABT-414 dose escalation used a modified continual reassessment method. Primary objectives were to assess ABT-414 safety, maximum tolerated dose (MTD), and recommended phase II dose (RPTD); secondary objectives included antitumor activity evaluation. RESULTS: As of April 2015, 19 Arm B patients were treated in 4 dose groups (0.5-1.5 mg/kg), and 27 Arm C patients were treated at 1.25 mg/kg. In Arms B/C, 10/17 patients had amplified EGFR. Most common grade 3/4 treatment-emergent adverse events in either arm were keratitis (11%/19%), γ-glutamyltransferase increase (16%/0%), convulsions (11%/0%), fatigue (11%/0%), and thrombocytopenia (11%/4%). ABT-414 MTD was 1.5 mg/kg in Arm B and was not reached in Arm C; RPTD is 1.25 mg/kg for both arms. Best objective responses were complete response (CR) in 3 patients and a partial response (PR) in 1 patient in Arm B, and 1 CR and 1 PR in Arm C patients (all confirmed responses were observed in patients with EGFR amplification).Objective response rate among EGFR-amplified subjects was 22.2% (6/27). CONCLUSIONS: RPTD for ABT-414 is 1.25 mg/kg for both combination therapy with TMZ rechallenge and monotherapy. ABT-414 demonstrated a unique safety profile including ocular AEs, and appears to have antitumor activity in recurrent GBM with EGFR amplification.
Source: Neuro-Oncology
Institutions: Austin Health, Olivia Newton-John Cancer Research Institute, Northwestern University, Columbia University Irving Medical Center, Herbert Irving Comprehensive Cancer Center, Columbia University, Endeavor Health, Erasmus MC, Erasmus MC Cancer Institute, South Texas Accelerated Research Therapeutics, AbbVie (United States), Dana-Farber Cancer Institute
Language: English
Subfield: Genetics
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W2340153564