title: Phase I ficlatuzumab monotherapy or with erlotinib for refractory advanced solid tumours and multiple myeloma.
abstract: BACKGROUND
  Ficlatuzumab, a humanised hepatocyte growth factor (HGF) IgG1κ inhibitory monoclonal antibody, was evaluated for recommended phase II dose (RP2D), safety, pharmacokinetics (PKs), antidrug antibody (ADA), pharmacodynamics (PDs) and antitumour activity as monotherapy or combined with erlotinib.
  
  
  METHODS
  Patients with solid tumours received ficlatuzumab 2, 5, 10 or 20 mg kg(-1) intravenously every 2 weeks (q2w). Additional patients were treated at the RP2D erlotinib.
  
  
  RESULTS
  Forty-one patients enrolled at doses ⩽20 mg kg(-1). Common adverse events (AEs) included peripheral oedema, fatigue and nausea. Three patients experienced grade ⩾3 treatment-related hyperkalaemia/hypokalaemia, diarrhoea or fatigue. Best overall response (44%) was stable disease (SD); median duration was 5.5 months (0.4-18.7 months). One patient has been on therapy with SD for >4 years. Pharmacokinetics of ficlatuzumab showed low clearance (0.17-0.26 ml h(-1) kg(-1)), a half-life of 6.8-9.4 days and dose-proportional exposure. Ficlatuzumab/erlotinib had no impact on the PK of either agent. No ADAs were detected. Ficlatuzumab increased serum HGF levels.
  
  
  CONCLUSIONS
  Recommended phase II dose is 20 mg kg(-1) q2w for ficlatuzumab monotherapy or with erlotinib. Preliminary antitumour activity and manageable AEs were observed. Pharmacokinetics were dose-proportional and consistent with other IgG therapeutics. Ficlatuzumab was not immunogenic, and serum HGF was a potential PD marker.
authors.affiliation: Clinical Research, South Texas Accelerated Research Therapeutics (START), 4383 Medical Drive, San Antonio, TX 78229, USA.
authors.forename: A
authors.initials: A
authors.lastname: Patnaik
authors.affiliation: Division of Hematology and Medical Oncology, Virginia G Piper Cancer Center, 10460 North 92nd Street, Suite 101, Scottsdale, AZ 85258, USA.
authors.forename: G J
authors.initials: GJ
authors.lastname: Weiss
authors.affiliation: Clinical Research, South Texas Accelerated Research Therapeutics (START), 4383 Medical Drive, San Antonio, TX 78229, USA.
authors.forename: K P
authors.initials: KP
authors.lastname: Papadopoulos
authors.affiliation: Hematology Division Internal Medicine Department, Ohio State University, 320 West 10th Avenue, Columbus, OH 43210, USA.
authors.forename: C C
authors.initials: CC
authors.lastname: Hofmeister
authors.affiliation: Division of Hematology and Medical Oncology, Virginia G Piper Cancer Center, 10460 North 92nd Street, Suite 101, Scottsdale, AZ 85258, USA.
authors.forename: R
authors.initials: R
authors.lastname: Tibes
authors.affiliation: Clinical Research, South Texas Accelerated Research Therapeutics (START), 4383 Medical Drive, San Antonio, TX 78229, USA.
authors.forename: A
authors.initials: A
authors.lastname: Tolcher
authors.affiliation: Merck, 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors.forename: R
authors.initials: R
authors.lastname: Isaacs
authors.affiliation: AVEO Pharmaceuticals, Inc., 75 Sidney Street, Cambridge, MA 02139, USA.
authors.forename: J
authors.initials: J
authors.lastname: Jac
authors.affiliation: AVEO Pharmaceuticals, Inc., 75 Sidney Street, Cambridge, MA 02139, USA.
authors.forename: M
authors.initials: M
authors.lastname: Han
authors.affiliation: AVEO Pharmaceuticals, Inc., 75 Sidney Street, Cambridge, MA 02139, USA.
authors.forename: F C
authors.initials: FC
authors.lastname: Payumo
authors.affiliation: AVEO Pharmaceuticals, Inc., 75 Sidney Street, Cambridge, MA 02139, USA.
authors.forename: M M
authors.initials: MM
authors.lastname: Cotreau
authors.affiliation: Division of Hematology and Medical Oncology, Virginia G Piper Cancer Center, 10460 North 92nd Street, Suite 101, Scottsdale, AZ 85258, USA.
authors.forename: R K
authors.initials: RK
authors.lastname: Ramanathan
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D015331:Cohort Studies; D000069347:Erlotinib Hydrochloride; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics; D011799:Quinazolines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics
chemical_list: D000911:Antibodies, Monoclonal; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; C583360:ficlatuzumab; D000069347:Erlotinib Hydrochloride