Efficacy and safety results of ABT-414 in combination with radiation and temozolomide in newly diagnosed glioblastoma

Abstract

Background: The purpose of this study was to determine the maximum tolerated dose (MTD), recommended phase II dose (RPTD), safety, and pharmacokinetics of ABT-414 plus radiation and temozolomide in newly diagnosed glioblastoma. ABT-414 is a first-in-class, tumor-specific antibody-drug conjugate that preferentially targets tumors expressing overactive epidermal growth factor receptor (EGFR).

Methods: In this multicenter phase I study, patients received 0.5-3.2 mg/kg ABT-414 every 2 weeks by intravenous infusion. EGFR alterations, O6-methylguanine-DNA methyltransferase (MGMT) promoter hypermethylation, and isocitrate dehydrogenase (IDH1) gene mutations were assessed in patient tumors. Distinct prognostic classes were assigned to patients based on a Molecular Classification Predictor model.

Results: As of January 7, 2016, forty-five patients were enrolled to receive ABT-414 plus radiation and temozolomide. The most common treatment emergent adverse events were ocular: blurred vision, dry eye, keratitis, photophobia, and eye pain. Ocular toxicity at any grade occurred in 40 patients and at grades 3/4 in 12 patients. RPTD and MTD were set at 2 mg/kg and 2.4 mg/kg, respectively. Among 38 patients with pretreatment tumor tested centrally, 39% harbored EGFR amplification, of which 73% had EGFRvIII mutation. Among patients with available tumor tissue (n = 30), 30% showed MGMT promoter methylation and none had IDH1 mutations. ABT-414 demonstrated an approximately dose proportional pharmacokinetic profile. The median duration of progression-free survival was 6.1 months; median overall survival has not been reached.

Conclusion: ABT-414 plus chemoradiation demonstrated an acceptable safety and pharmacokinetic profile in newly diagnosed glioblastoma. Randomized studies are ongoing to determine efficacy in newly diagnosed (NCT02573324) and recurrent glioblastoma (NCT02343406).

Keywords: ABT-414; EGFR; antibody-drug conjugate; glioblastoma; phase.

Fig. 1

Study design: Arm A and expanded cohort A. C, cycle; D, day; DLT, dose-limiting toxicity; F/U, follow-up; RT, radiation therapy; TMZ, temozolomide; W, week; ▲, tumor assessment screening; C1D1, every other cycle post C1D1 and final visit (if not within 3 weeks).

Fig. 2

ABT-414 PK exposure vs dose following ABT-414 dosing in week 1. (A) ABT-414 peak concentration (C_max) versus ABT-414 dose. (B) ABT-414 area under the concentration–time curve from time zero to 14 days (AUC_{14 days}) vs ABT-414 dose. Values are presented as mean±SD. AUC, area under the curve; C_max, maximum concentration.

Fig. 3

Concentration–time profiles for ABT-414, total ABT-806, and cys-mcMMAF. The results represent observations following 2 mg/kg ABT-414 dose administration on day 1 of weeks 1 and 5. Values are presented as mean±SD.