title: Targeted MET inhibition in castration-resistant prostate cancer: a randomized phase II study and biomarker analysis with rilotumumab plus mitoxantrone and prednisone.
abstract: OBJECTIVE
  To evaluate the efficacy, safety, biomarkers, and pharmacokinetics of rilotumumab, a fully human, monoclonal antibody against hepatocyte growth factor (HGF)/scatter factor, combined with mitoxantrone and prednisone (MP) in patients with castration-resistant prostate cancer (CRPC).
  
  
  METHODS
  This double-blinded phase II study randomized (1:1:1) patients with progressive, taxane-refractory CRPC to receive MP (12 mg/m(2) i.v. day 1, 5 mg twice a day orally days 1-21, respectively) plus 15 mg/kg rilotumumab, 7.5 mg/kg rilotumumab, or placebo (i.v. day 1) every 3 weeks. The primary endpoint was overall survival (OS).
  
  
  RESULTS
  One hundred and forty-four patients were randomized. Median OS was 12.2 versus 11.1 months [HR, 1.10; 80% confidence interval (CI), 0.82-1.48] in the combined rilotumumab versus control arms. Median progression-free survival was 3.0 versus 2.9 months (HR, 1.02; 80% CI, 0.79-1.31). Treatment appeared well tolerated with peripheral edema (24% vs. 8%) being more common with rilotumumab. A trend toward unfavorable OS was observed in patients with high tumor MET expression regardless of treatment. Soluble MET levels increased in all treatment arms. Total HGF levels increased in the rilotumumab arms. Rilotumumab showed linear pharmacokinetics when co-administered with MP.
  
  
  CONCLUSIONS
  Rilotumumab plus MP had manageable toxicities and showed no efficacy improvements in this estimation study. High tumor MET expression may identify patients with CRPC with poorer prognosis.
authors.affiliation: University of California San Francisco Helen Diller Family Comprehensive Cancer Center, San Francisco, CA 94115, USA. ryanc@medicine.ucsf.edu
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Ryan
authors.forename: Mark
authors.initials: M
authors.lastname: Rosenthal
authors.forename: Siobhan
authors.initials: S
authors.lastname: Ng
authors.forename: Joshi
authors.initials: J
authors.lastname: Alumkal
authors.forename: Joel
authors.initials: J
authors.lastname: Picus
authors.forename: Gwenaëlle
authors.initials: G
authors.lastname: Gravis
authors.forename: Karim
authors.initials: K
authors.lastname: Fizazi
authors.forename: Frédéric
authors.initials: F
authors.lastname: Forget
authors.forename: Jean-Pascal
authors.initials: JP
authors.lastname: Machiels
authors.forename: Sandy
authors.initials: S
authors.lastname: Srinivas
authors.forename: Min
authors.initials: M
authors.lastname: Zhu
authors.forename: Rui
authors.initials: R
authors.lastname: Tang
authors.forename: Kelly S
authors.initials: KS
authors.lastname: Oliner
authors.forename: Yizhou
authors.initials: Y
authors.lastname: Jiang
authors.forename: Elwyn
authors.initials: E
authors.lastname: Loh
authors.forename: Sarita
authors.initials: S
authors.lastname: Dubey
authors.forename: Winald R
authors.initials: WR
authors.lastname: Gerritsen
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000493:pharmacokinetics; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D008942:Mitoxantrone / Q000008:administration & dosage / Q000493:pharmacokinetics; D058990:Molecular Targeted Therapy; D009919:Orchiectomy; D011241:Prednisone / Q000008:administration & dosage / Q000493:pharmacokinetics; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D014408:Biomarkers, Tumor; C524459:rilotumumab; D008942:Mitoxantrone; D019859:Proto-Oncogene Proteins c-met; D011241:Prednisone