Efficacy and safety results of ABT-414 in combination with radiation and temozolomide in newly diagnosed glioblastoma. Academic Article uri icon

abstract

  • 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).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.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.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).

authors

  • Reardon, DA
  • Lassman, AB
  • van den Bent, M
  • Kumthekar, P
  • Merrell, R
  • Scott, Andrew M
  • Fichtel, L
  • Sulman, EP
  • Gomez, E
  • Fischer, J
  • Lee, H-J
  • Munasinghe, W
  • Xiong, H
  • Mandich, H
  • Roberts-Rapp, L
  • Ansell, P
  • Holen, KD
  • Gan, Hui K

publication date

  • 2017