title: 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.
  
  
  CONCLUSIONS
  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.affiliation: Center for Neuro-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts; Department of Neurology & Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York; Neuro-Oncology Unit, Erasmus MC Cancer Center, Rotterdam, the Netherlands; Department of Neurology, Northwestern University, Chicago, Illinois; Department of Neurology, NorthShore University HealthSystem, Evanston, Illinois; Department of Medical Oncology, Austin Health and Olivia Newton-John Cancer Research Institute, Melbourne, Victoria, Australia; School of Cancer Medicine, La Trobe University School of Cancer Medicine, Melbourne, Victoria, Australia; South Texas Accelerated Research Therapeutics (START), San Antonio, Texas; Department of Radiation Oncology, The University of Texas M.D.Anderson Cancer Center, Houston, Texas; AbbVie Inc., North Chicago, Illinois; Department of Medicine, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: David A
authors.initials: DA
authors.lastname: Reardon
authors.affiliation: Center for Neuro-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts; Department of Neurology & Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York; Neuro-Oncology Unit, Erasmus MC Cancer Center, Rotterdam, the Netherlands; Department of Neurology, Northwestern University, Chicago, Illinois; Department of Neurology, NorthShore University HealthSystem, Evanston, Illinois; Department of Medical Oncology, Austin Health and Olivia Newton-John Cancer Research Institute, Melbourne, Victoria, Australia; School of Cancer Medicine, La Trobe University School of Cancer Medicine, Melbourne, Victoria, Australia; South Texas Accelerated Research Therapeutics (START), San Antonio, Texas; Department of Radiation Oncology, The University of Texas M.D.Anderson Cancer Center, Houston, Texas; AbbVie Inc., North Chicago, Illinois; Department of Medicine, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Andrew B
authors.initials: AB
authors.lastname: Lassman
authors.affiliation: Center for Neuro-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts; Department of Neurology & Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York; Neuro-Oncology Unit, Erasmus MC Cancer Center, Rotterdam, the Netherlands; Department of Neurology, Northwestern University, Chicago, Illinois; Department of Neurology, NorthShore University HealthSystem, Evanston, Illinois; Department of Medical Oncology, Austin Health and Olivia Newton-John Cancer Research Institute, Melbourne, Victoria, Australia; School of Cancer Medicine, La Trobe University School of Cancer Medicine, Melbourne, Victoria, Australia; South Texas Accelerated Research Therapeutics (START), San Antonio, Texas; Department of Radiation Oncology, The University of Texas M.D.Anderson Cancer Center, Houston, Texas; AbbVie Inc., North Chicago, Illinois; Department of Medicine, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Martin
authors.initials: M
authors.lastname: van den Bent
authors.affiliation: Center for Neuro-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts; Department of Neurology & Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York; Neuro-Oncology Unit, Erasmus MC Cancer Center, Rotterdam, the Netherlands; Department of Neurology, Northwestern University, Chicago, Illinois; Department of Neurology, NorthShore University HealthSystem, Evanston, Illinois; Department of Medical Oncology, Austin Health and Olivia Newton-John Cancer Research Institute, Melbourne, Victoria, Australia; School of Cancer Medicine, La Trobe University School of Cancer Medicine, Melbourne, Victoria, Australia; South Texas Accelerated Research Therapeutics (START), San Antonio, Texas; Department of Radiation Oncology, The University of Texas M.D.Anderson Cancer Center, Houston, Texas; AbbVie Inc., North Chicago, Illinois; Department of Medicine, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Priya
authors.initials: P
authors.lastname: Kumthekar
authors.affiliation: Center for Neuro-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts; Department of Neurology & Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York; Neuro-Oncology Unit, Erasmus MC Cancer Center, Rotterdam, the Netherlands; Department of Neurology, Northwestern University, Chicago, Illinois; Department of Neurology, NorthShore University HealthSystem, Evanston, Illinois; Department of Medical Oncology, Austin Health and Olivia Newton-John Cancer Research Institute, Melbourne, Victoria, Australia; School of Cancer Medicine, La Trobe University School of Cancer Medicine, Melbourne, Victoria, Australia; South Texas Accelerated Research Therapeutics (START), San Antonio, Texas; Department of Radiation Oncology, The University of Texas M.D.Anderson Cancer Center, Houston, Texas; AbbVie Inc., North Chicago, Illinois; Department of Medicine, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Ryan
authors.initials: R
authors.lastname: Merrell
authors.affiliation: Center for Neuro-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts; Department of Neurology & Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York; Neuro-Oncology Unit, Erasmus MC Cancer Center, Rotterdam, the Netherlands; Department of Neurology, Northwestern University, Chicago, Illinois; Department of Neurology, NorthShore University HealthSystem, Evanston, Illinois; Department of Medical Oncology, Austin Health and Olivia Newton-John Cancer Research Institute, Melbourne, Victoria, Australia; School of Cancer Medicine, La Trobe University School of Cancer Medicine, Melbourne, Victoria, Australia; South Texas Accelerated Research Therapeutics (START), San Antonio, Texas; Department of Radiation Oncology, The University of Texas M.D.Anderson Cancer Center, Houston, Texas; AbbVie Inc., North Chicago, Illinois; Department of Medicine, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Scott
authors.affiliation: Center for Neuro-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts; Department of Neurology & Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York; Neuro-Oncology Unit, Erasmus MC Cancer Center, Rotterdam, the Netherlands; Department of Neurology, Northwestern University, Chicago, Illinois; Department of Neurology, NorthShore University HealthSystem, Evanston, Illinois; Department of Medical Oncology, Austin Health and Olivia Newton-John Cancer Research Institute, Melbourne, Victoria, Australia; School of Cancer Medicine, La Trobe University School of Cancer Medicine, Melbourne, Victoria, Australia; South Texas Accelerated Research Therapeutics (START), San Antonio, Texas; Department of Radiation Oncology, The University of Texas M.D.Anderson Cancer Center, Houston, Texas; AbbVie Inc., North Chicago, Illinois; Department of Medicine, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Lisa
authors.initials: L
authors.lastname: Fichtel
authors.affiliation: Center for Neuro-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts; Department of Neurology & Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York; Neuro-Oncology Unit, Erasmus MC Cancer Center, Rotterdam, the Netherlands; Department of Neurology, Northwestern University, Chicago, Illinois; Department of Neurology, NorthShore University HealthSystem, Evanston, Illinois; Department of Medical Oncology, Austin Health and Olivia Newton-John Cancer Research Institute, Melbourne, Victoria, Australia; School of Cancer Medicine, La Trobe University School of Cancer Medicine, Melbourne, Victoria, Australia; South Texas Accelerated Research Therapeutics (START), San Antonio, Texas; Department of Radiation Oncology, The University of Texas M.D.Anderson Cancer Center, Houston, Texas; AbbVie Inc., North Chicago, Illinois; Department of Medicine, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Erik P
authors.initials: EP
authors.lastname: Sulman
authors.affiliation: Center for Neuro-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts; Department of Neurology & Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York; Neuro-Oncology Unit, Erasmus MC Cancer Center, Rotterdam, the Netherlands; Department of Neurology, Northwestern University, Chicago, Illinois; Department of Neurology, NorthShore University HealthSystem, Evanston, Illinois; Department of Medical Oncology, Austin Health and Olivia Newton-John Cancer Research Institute, Melbourne, Victoria, Australia; School of Cancer Medicine, La Trobe University School of Cancer Medicine, Melbourne, Victoria, Australia; South Texas Accelerated Research Therapeutics (START), San Antonio, Texas; Department of Radiation Oncology, The University of Texas M.D.Anderson Cancer Center, Houston, Texas; AbbVie Inc., North Chicago, Illinois; Department of Medicine, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Erica
authors.initials: E
authors.lastname: Gomez
authors.affiliation: Center for Neuro-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts; Department of Neurology & Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York; Neuro-Oncology Unit, Erasmus MC Cancer Center, Rotterdam, the Netherlands; Department of Neurology, Northwestern University, Chicago, Illinois; Department of Neurology, NorthShore University HealthSystem, Evanston, Illinois; Department of Medical Oncology, Austin Health and Olivia Newton-John Cancer Research Institute, Melbourne, Victoria, Australia; School of Cancer Medicine, La Trobe University School of Cancer Medicine, Melbourne, Victoria, Australia; South Texas Accelerated Research Therapeutics (START), San Antonio, Texas; Department of Radiation Oncology, The University of Texas M.D.Anderson Cancer Center, Houston, Texas; AbbVie Inc., North Chicago, Illinois; Department of Medicine, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: JuDee
authors.initials: J
authors.lastname: Fischer
authors.affiliation: Center for Neuro-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts; Department of Neurology & Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York; Neuro-Oncology Unit, Erasmus MC Cancer Center, Rotterdam, the Netherlands; Department of Neurology, Northwestern University, Chicago, Illinois; Department of Neurology, NorthShore University HealthSystem, Evanston, Illinois; Department of Medical Oncology, Austin Health and Olivia Newton-John Cancer Research Institute, Melbourne, Victoria, Australia; School of Cancer Medicine, La Trobe University School of Cancer Medicine, Melbourne, Victoria, Australia; South Texas Accelerated Research Therapeutics (START), San Antonio, Texas; Department of Radiation Oncology, The University of Texas M.D.Anderson Cancer Center, Houston, Texas; AbbVie Inc., North Chicago, Illinois; Department of Medicine, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Ho-Jin
authors.initials: HJ
authors.lastname: Lee
authors.affiliation: Center for Neuro-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts; Department of Neurology & Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York; Neuro-Oncology Unit, Erasmus MC Cancer Center, Rotterdam, the Netherlands; Department of Neurology, Northwestern University, Chicago, Illinois; Department of Neurology, NorthShore University HealthSystem, Evanston, Illinois; Department of Medical Oncology, Austin Health and Olivia Newton-John Cancer Research Institute, Melbourne, Victoria, Australia; School of Cancer Medicine, La Trobe University School of Cancer Medicine, Melbourne, Victoria, Australia; South Texas Accelerated Research Therapeutics (START), San Antonio, Texas; Department of Radiation Oncology, The University of Texas M.D.Anderson Cancer Center, Houston, Texas; AbbVie Inc., North Chicago, Illinois; Department of Medicine, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Wijith
authors.initials: W
authors.lastname: Munasinghe
authors.affiliation: Center for Neuro-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts; Department of Neurology & Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York; Neuro-Oncology Unit, Erasmus MC Cancer Center, Rotterdam, the Netherlands; Department of Neurology, Northwestern University, Chicago, Illinois; Department of Neurology, NorthShore University HealthSystem, Evanston, Illinois; Department of Medical Oncology, Austin Health and Olivia Newton-John Cancer Research Institute, Melbourne, Victoria, Australia; School of Cancer Medicine, La Trobe University School of Cancer Medicine, Melbourne, Victoria, Australia; South Texas Accelerated Research Therapeutics (START), San Antonio, Texas; Department of Radiation Oncology, The University of Texas M.D.Anderson Cancer Center, Houston, Texas; AbbVie Inc., North Chicago, Illinois; Department of Medicine, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Hao
authors.initials: H
authors.lastname: Xiong
authors.affiliation: Center for Neuro-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts; Department of Neurology & Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York; Neuro-Oncology Unit, Erasmus MC Cancer Center, Rotterdam, the Netherlands; Department of Neurology, Northwestern University, Chicago, Illinois; Department of Neurology, NorthShore University HealthSystem, Evanston, Illinois; Department of Medical Oncology, Austin Health and Olivia Newton-John Cancer Research Institute, Melbourne, Victoria, Australia; School of Cancer Medicine, La Trobe University School of Cancer Medicine, Melbourne, Victoria, Australia; South Texas Accelerated Research Therapeutics (START), San Antonio, Texas; Department of Radiation Oncology, The University of Texas M.D.Anderson Cancer Center, Houston, Texas; AbbVie Inc., North Chicago, Illinois; Department of Medicine, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Helen
authors.initials: H
authors.lastname: Mandich
authors.affiliation: Center for Neuro-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts; Department of Neurology & Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York; Neuro-Oncology Unit, Erasmus MC Cancer Center, Rotterdam, the Netherlands; Department of Neurology, Northwestern University, Chicago, Illinois; Department of Neurology, NorthShore University HealthSystem, Evanston, Illinois; Department of Medical Oncology, Austin Health and Olivia Newton-John Cancer Research Institute, Melbourne, Victoria, Australia; School of Cancer Medicine, La Trobe University School of Cancer Medicine, Melbourne, Victoria, Australia; South Texas Accelerated Research Therapeutics (START), San Antonio, Texas; Department of Radiation Oncology, The University of Texas M.D.Anderson Cancer Center, Houston, Texas; AbbVie Inc., North Chicago, Illinois; Department of Medicine, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Lisa
authors.initials: L
authors.lastname: Roberts-Rapp
authors.affiliation: Center for Neuro-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts; Department of Neurology & Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York; Neuro-Oncology Unit, Erasmus MC Cancer Center, Rotterdam, the Netherlands; Department of Neurology, Northwestern University, Chicago, Illinois; Department of Neurology, NorthShore University HealthSystem, Evanston, Illinois; Department of Medical Oncology, Austin Health and Olivia Newton-John Cancer Research Institute, Melbourne, Victoria, Australia; School of Cancer Medicine, La Trobe University School of Cancer Medicine, Melbourne, Victoria, Australia; South Texas Accelerated Research Therapeutics (START), San Antonio, Texas; Department of Radiation Oncology, The University of Texas M.D.Anderson Cancer Center, Houston, Texas; AbbVie Inc., North Chicago, Illinois; Department of Medicine, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Peter
authors.initials: P
authors.lastname: Ansell
authors.affiliation: Center for Neuro-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts; Department of Neurology & Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York; Neuro-Oncology Unit, Erasmus MC Cancer Center, Rotterdam, the Netherlands; Department of Neurology, Northwestern University, Chicago, Illinois; Department of Neurology, NorthShore University HealthSystem, Evanston, Illinois; Department of Medical Oncology, Austin Health and Olivia Newton-John Cancer Research Institute, Melbourne, Victoria, Australia; School of Cancer Medicine, La Trobe University School of Cancer Medicine, Melbourne, Victoria, Australia; South Texas Accelerated Research Therapeutics (START), San Antonio, Texas; Department of Radiation Oncology, The University of Texas M.D.Anderson Cancer Center, Houston, Texas; AbbVie Inc., North Chicago, Illinois; Department of Medicine, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Kyle D
authors.initials: KD
authors.lastname: Holen
authors.affiliation: Center for Neuro-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts; Department of Neurology & Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York; Neuro-Oncology Unit, Erasmus MC Cancer Center, Rotterdam, the Netherlands; Department of Neurology, Northwestern University, Chicago, Illinois; Department of Neurology, NorthShore University HealthSystem, Evanston, Illinois; Department of Medical Oncology, Austin Health and Olivia Newton-John Cancer Research Institute, Melbourne, Victoria, Australia; School of Cancer Medicine, La Trobe University School of Cancer Medicine, Melbourne, Victoria, Australia; South Texas Accelerated Research Therapeutics (START), San Antonio, Texas; Department of Radiation Oncology, The University of Texas M.D.Anderson Cancer Center, Houston, Texas; AbbVie Inc., North Chicago, Illinois; Department of Medicine, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Hui K
authors.initials: HK
authors.lastname: Gan
mesh_terms: D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000378:metabolism; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000532:radiotherapy*; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D018572:Disease-Free Survival; D004359:Drug Therapy, Combination; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy* / Q000532:radiotherapy*; D006801:Humans; D018796:Immunoconjugates / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D000077204:Temozolomide; D016896:Treatment Outcome
chemical_list: C000620234:ABT-414; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D018796:Immunoconjugates; D003606:Dacarbazine; D000077204:Temozolomide
keywords: ABT-414; EGFR; antibody-drug conjugate; glioblastoma; phase