title: Onartuzumab with or without bevacizumab in combination with weekly paclitaxel does not prolong QTc or adversely affect other ECG parameters in patients with locally recurrent or metastatic triple-negative breast cancer.
abstract: OBJECTIVE
  The potential effect of onartuzumab, when administered with or without bevacizumab in combination with weekly paclitaxel, on the corrected QT interval (QTc) and other electrocardiogram (ECG) parameters, was investigated in a randomized, phase 2 study OAM4861g of first- or second-line therapy in patients with locally recurrent or metastatic triple-negative breast cancer.
  
  
  METHODS
  Triplicate 12-lead ECGs were recorded at screening, pre- and post-dose on day 1 of cycles 1, 2, and 4, and at the study drug discontinuation visit (SDDV). Onartuzumab serum samples were collected pre- and post-dose on day 1 of cycles 1-4 and at the SDDV. Fridericia's correction was applied to QT recordings (QTcF), and change from baseline (ΔQTcF) was calculated. Post-baseline measurements were reported as baseline-adjusted control arm (placebo plus bevacizumab plus paclitaxel)-corrected values (ΔΔQTcF). Categorical ECG findings were noted. Linear mixed effects modeling evaluated a potential concentration-ΔQTcF relationship.
  
  
  RESULTS
  Out of 185 enrolled patients, 165 patients had ECG-evaluable data for analyses. Similar ΔQTcF and ΔΔQTcF values were observed across all treatment arms, with mean increase <10 and <7 ms, respectively, across all time points. Similar changes in heart rate, PR interval, and QRS duration were noted across all treatment arms. Incidences of abnormal ECG findings of clinical interest were comparable in the onartuzumab-containing arms and the control arm. No concentration-ΔQTcF relationship was evident at onartuzumab serum concentrations up to 1,200 μg/ml.
  
  
  CONCLUSIONS
  These data suggest that onartuzumab, at the dose and exposures studied in this clinical trial, does not meaningfully affect the QTcF interval.
authors.affiliation: Clinical Pharmacology, Genentech, Inc., 1 DNA Way, South San Francisco, CA, 94080, USA.
authors.forename: Marie T
authors.initials: MT
authors.lastname: Borin
authors.forename: Meng
authors.initials: M
authors.lastname: Chen
authors.forename: Simonetta
authors.initials: S
authors.lastname: Mocci
authors.forename: Igor
authors.initials: I
authors.lastname: Rubets
authors.forename: Jason
authors.initials: J
authors.lastname: Chittenden
authors.forename: Wassim
authors.initials: W
authors.lastname: Aldairy
authors.forename: Mark
authors.initials: M
authors.lastname: Stroh
mesh_terms: D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000627:therapeutic use; D000068258:Bevacizumab; D001943:Breast Neoplasms / Q000150:complications* / Q000188:drug therapy; D004311:Double-Blind Method; D004562:Electrocardiography / Q000187:drug effects*; D005260:Female; D006801:Humans; D008133:Long QT Syndrome / Q000139:chemically induced* / Q000503:physiopathology; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009364:Neoplasm Recurrence, Local; D017239:Paclitaxel / Q000008:administration & dosage
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000972:Antineoplastic Agents, Phytogenic; D000068258:Bevacizumab; C584058:onartuzumab; D017239:Paclitaxel