title: A phase 1 study of ABT-806 in subjects with advanced solid tumors.
abstract: OBJECTIVE
  ABT-806, a humanized recombinant monoclonal antibody, binds a unique epidermal growth factor receptor (EGFR) epitope exposed in the EGFRde2-7 (EGFRvIII) deletion mutant and other EGFR proteins in the activated state. This phase I study evaluated the safety, pharmacokinetics, and recommended phase two dose (RP2D) of ABT-806 in patients with solid tumors that commonly overexpress activated EGFR or EGFRvlll.
  
  
  METHODS
  Patients with advanced solid tumors, including glioblastoma, were eligible. Following a dose escalation phase, expanded safety cohorts of patients with solid tumors or EGFR-amplified glioblastoma were enrolled. Adverse events (AEs) were graded by National Cancer Institute Common Terminology Criteria for Adverse Events v4.0; tumor response was assessed by Response Evaluation Criteria in Solid Tumors v1.1. EGFR protein expression was quantified by immunohistochemistry.
  
  
  RESULTS
  49 patients were treated. Frequent AEs (≥10 %) possibly/probably related to ABT-806 were fatigue (18 %), nausea (16 %), dermatitis acneiform (12 %), and vomiting (10 %). Only one dose-limiting toxicity (grade three morbilliform rash) occurred. The RP2D was the pre-specified highest dose (24 mg/kg). Systemic exposures were dose proportional between 2 and 24 mg/kg. Median time to progression was 55 days (95 % confidence interval, 53-57) in all patients and 43 days (22-57) for glioblastoma patients. No objective responses occurred; however, two patients had prolonged stable disease. An EGFR-amplified penile cancer patient has stable disease lasting over 2.5 years.
  
  
  CONCLUSIONS
  ABT-806 has unique pharmacokinetic and safety profiles. Toxicities were infrequent and typically low grade at the RP2D. Linear ABT-806 pharmacokinetics suggest lack of significant binding to wild-type EGFR in normal tissues.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA, jcleary@partners.org.
authors.forename: James M
authors.initials: JM
authors.lastname: Cleary
authors.forename: David A
authors.initials: DA
authors.lastname: Reardon
authors.forename: Nilofer
authors.initials: N
authors.lastname: Azad
authors.forename: Leena
authors.initials: L
authors.lastname: Gandhi
authors.forename: Geoffrey I
authors.initials: GI
authors.lastname: Shapiro
authors.forename: Jorge
authors.initials: J
authors.lastname: Chaves
authors.forename: Michelle
authors.initials: M
authors.lastname: Pedersen
authors.forename: Peter
authors.initials: P
authors.lastname: Ansell
authors.forename: William
authors.initials: W
authors.lastname: Ames
authors.forename: Hao
authors.initials: H
authors.lastname: Xiong
authors.forename: Wijith
authors.initials: W
authors.lastname: Munasinghe
authors.forename: Matt
authors.initials: M
authors.lastname: Dudley
authors.forename: Edward B
authors.initials: EB
authors.lastname: Reilly
authors.forename: Kyle
authors.initials: K
authors.lastname: Holen
authors.forename: Rod
authors.initials: R
authors.lastname: Humerickhouse
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D019540:Area Under Curve; D014408:Biomarkers, Tumor / Q000378:metabolism; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology*
chemical_list: D000911:Antibodies, Monoclonal; D014408:Biomarkers, Tumor; C518939:monoclonal antibody 806; D066246:ErbB Receptors