title: Evaluation of the effect of the EGFR antibody-drug conjugate ABT-414 on QT interval prolongation in patients with advanced solid tumors likely to over-express EGFR.
abstract: OBJECTIVE
  ABT-414 is an antibody-drug conjugate (ADC) being developed for the treatment of tumors harboring amplification of the epidermal growth factor receptor (EGFR). This study evaluated the potential of ABT-414 to prolong the QT interval as part of the initial phase 1 study (NCT01741727).
  
  
  METHODS
  Data from patients who received ABT-414 monotherapy at a dose of 1-4 mg/kg once every 3 weeks or 1 or 1.5 mg/kg weekly for 2 out of every 3 weeks (alternate schedule) by intravenous infusion were included in the analysis of triplicate 12-lead ECGs obtained before dosing and through 168 h after dosing. Data from time-matched pharmacokinetic samples and QT interval assessments were evaluated using linear mixed-effects modeling to determine the effects of ABT-414, total ABT-806, and cysteine-maleimidocaproyl monomethyl auristatin F (Cys-mcMMAF) on the QT interval corrected using Fridericia's formula (QTcF).
  
  
  RESULTS
  Fifty-one patients were included in the analyses. ABT-414 had no clinically meaningful effect on QTcF. Using pooled data from doses ≥2 mg/kg, the estimated mean ∆QTcF reached a maximum of 4.30 ms after dosing, with a one-sided 95% upper confidence bound of 8.32 ms. The exposure-response analysis showed no statistically significant relationship between ΔQTcF and the concentration of any analyte (P > 0.05). No patient had a QTcF value >480 ms or a ∆QTcF value >30 ms.
  
  
  CONCLUSIONS
  ABT-414 had no clinically meaningful effect on the QTcF interval at doses being evaluated for treatment of patients with solid tumors.
authors.affiliation: Abbvie, Data and Statistical Sciences, 1 North Waukegan Road, North Chicago, IL, 60064, USA.
authors.forename: Wijith P
authors.initials: WP
authors.lastname: Munasinghe
authors.affiliation: AbbVie, Clinical Pharmacology and Pharmacometrics, 1 North Waukegan Road, North Chicago, IL, 60064, USA.
authors.forename: Rajendar K
authors.initials: RK
authors.lastname: Mittapalli
authors.affiliation: Abbvie, Data and Statistical Sciences, 1 North Waukegan Road, North Chicago, IL, 60064, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Li
authors.affiliation: Abbvie, Data and Statistical Sciences, 1 North Waukegan Road, North Chicago, IL, 60064, USA.
authors.forename: David M
authors.initials: DM
authors.lastname: Hoffman
authors.affiliation: AbbVie, Oncology Development, 1 North Waukegan Road, North Chicago, IL, 60064, USA.
authors.forename: Kyle D
authors.initials: KD
authors.lastname: Holen
authors.affiliation: AbbVie, Clinical Pharmacology and Pharmacometrics, 1 North Waukegan Road, North Chicago, IL, 60064, USA.
authors.forename: Rajeev M
authors.initials: RM
authors.lastname: Menon
authors.affiliation: AbbVie, Clinical Pharmacology and Pharmacometrics, 1 North Waukegan Road, North Chicago, IL, 60064, USA. hao.xiong@abbvie.com.
authors.forename: Hao
authors.initials: H
authors.lastname: Xiong
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D061067:Antibodies, Monoclonal, Humanized / Q000009:adverse effects; D000970:Antineoplastic Agents / Q000009:adverse effects*; D001711:Biotransformation; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography / Q000187:drug effects; D066246:ErbB Receptors / Q000096:biosynthesis* / Q000235:genetics; D005260:Female; D006801:Humans; D018796:Immunoconjugates / Q000009:adverse effects; D007262:Infusions, Intravenous; D008133:Long QT Syndrome / Q000139:chemically induced*; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000150:complications* / Q000188:drug therapy / Q000235:genetics*; D047428:Protein Kinase Inhibitors / Q000009:adverse effects*
chemical_list: C000620234:ABT-414; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D018796:Immunoconjugates; D047428:Protein Kinase Inhibitors; C512478:EGFR protein, human; D066246:ErbB Receptors
keywords: ABT-414; Antibody-drug conjugate; ECG; EGFR; QT interval; Solid tumor