title: Phase 1 dose-escalation trial evaluating the combination of the selective MET (mesenchymal-epithelial transition factor) inhibitor tivantinib (ARQ 197) plus erlotinib.
abstract: BACKGROUND
  Amplification of the mesenchymal-epithelial transition factor (MET) gene can promote tumor resistance to epidermal growth factor receptor (EGFR) inhibition. Dual EGFR-MET inhibition may overcome this resistance. Tivantinib (ARQ 197) is a selective, oral, non-ATP-competitive, small-molecule inhibitor of the MET receptor tyrosine kinase. This phase 1 trial assessed the safety, pharmacokinetics, and preliminary antitumor activity of tivantinib combined with the EGFR inhibitor erlotinib.
  
  
  METHODS
  Patients with advanced solid malignancies were administered oral tivantinib at escalating doses of 120, 240, 360, and 480 mg twice daily (BID) plus 150 mg erlotinib once daily (QD). Single or multiple intrapatient dose escalation was planned in the absence of dose-limiting toxicity in the first cycle of therapy (21 days).
  
  
  RESULTS
  Thirty-two patients received combination treatment. Tivantinib serum concentrations were not dose-proportional. The most common (≥ 20%) adverse events (AEs) regardless of causality included rash (n = 17), fatigue (n = 12), nausea (n = 10), abdominal pain (n = 10), diarrhea (n = 9), bradycardia (n = 9), and anemia (n = 7). AEs considered related to study treatment occurred in 28 patients (87.5%), and 5 patients (15.6%) had treatment-related serious AEs, including neutropenia, leukopenia, syncope, sinus bradycardia, and sick sinus syndrome. Fifteen of 32 patients (46.8%) had a partial response (n = 1) or stable disease (n = 14) as assessed by Response Evaluation Criteria in Solid Tumors. Six of 8 patients with nonsmall cell lung cancer achieved stable disease. The recommended phase 2 dose is tivantinib 360 mg BID plus erlotinib 150 mg QD.
  
  
  CONCLUSIONS
  Tivantinib plus erlotinib was well tolerated with encouraging clinical activity, especially in patients with nonsmall cell lung cancer.
authors.affiliation: David Geffen School of Medicine, University of California Los Angeles Medical Center, Los Angeles, California, USA. jwgoldman@mednet.ucla.edu
authors.forename: Jonathan W
authors.initials: JW
authors.lastname: Goldman
authors.forename: Isett
authors.initials: I
authors.lastname: Laux
authors.forename: Feng
authors.initials: F
authors.lastname: Chai
authors.forename: Ronald E
authors.initials: RE
authors.lastname: Savage
authors.forename: Dora
authors.initials: D
authors.lastname: Ferrari
authors.forename: Edward G
authors.initials: EG
authors.lastname: Garmey
authors.forename: Richard G
authors.initials: RG
authors.lastname: Just
authors.forename: Lee S
authors.initials: LS
authors.lastname: Rosen
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D000069347:Erlotinib Hydrochloride; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors*; D011760:Pyrrolidinones / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D011799:Quinazolines / Q000008:administration & dosage*; D011804:Quinolines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics
chemical_list: C551661:ARQ 197; D011760:Pyrrolidinones; D011799:Quinazolines; D011804:Quinolines; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors; D019859:Proto-Oncogene Proteins c-met