title: A randomised non-comparative phase II trial of cixutumumab (IMC-A12) or ramucirumab (IMC-1121B) plus mitoxantrone and prednisone in men with metastatic docetaxel-pretreated castration-resistant prostate cancer.
abstract: BACKGROUND
  Cixutumumab, a human monoclonal antibody (HuMAb), targets the insulin-like growth factor receptor. Ramucirumab is a recombinant HuMAb that binds to vascular endothelial growth factor receptor-2. A non-comparative randomised phase II study evaluated cixutumumab or ramucirumab plus mitoxantrone and prednisone (MP) in metastatic castration-resistant prostate cancer (mCRPC).
  
  
  METHODS
  Men with progressive mCRPC during or after docetaxel therapy received mitoxantrone 12 mg/m(2) on day 1 and prednisone 5mg twice daily and were randomised 1:1 to receive either cixutumumab or ramucirumab 6 mg/kg intravenously weekly in a 21-day cycle. Primary end-point was composite progression-free survival (cPFS). Secondary end-points included safety, response, radiographic progression-free survival (PFS) and overall survival (OS). Sample size was based on a 50% increase in median cPFS from 2.6 (MP) to 3.9 months (either combination).
  
  
  RESULTS
  132 men were treated (66 per arm). Median cPFS was 4.1 months (95% confidence interval (CI), 2.2-5.6) for cixutumumab and 6.7 months (95% CI, 4.5-8.3) for ramucirumab. Median time to radiographic progression was 7.5 months for cixutumumab and 10.2 months for ramucirumab, with a median OS of 10.8 and 13.0 months, respectively. Fatigue was the most frequent adverse event (AE). Incidence of most non-haematologic grade 3-4 AEs was <10% on both arms. Grade 3 cardiac dysfunction occurred in 7.6% of patients on ramucirumab.
  
  
  CONCLUSIONS
  Combinations of cixutumumab or ramucirumab plus MP were feasible and associated with moderate toxicities in docetaxel-pretreated men with mCRPC. Of the two regimens, the ramucirumab regimen is worthy of further testing based on the observed cPFS relative to the historical control.
authors.affiliation: University of Michigan Comprehensive Cancer Center, Ann Arbor, MI, United States. Electronic address: mahahuss@umich.edu.
authors.forename: Maha
authors.initials: M
authors.lastname: Hussain
authors.affiliation: Memorial Sloan-Kettering, New York, NY, United States.
authors.forename: Dana
authors.initials: D
authors.lastname: Rathkopf
authors.affiliation: University of Wisconsin, Carbone Cancer Center, Madison, WI, United States.
authors.forename: Glenn
authors.initials: G
authors.lastname: Liu
authors.affiliation: Duke Cancer Institute and Duke Prostate Center, Duke University, Durham, NC, United States.
authors.forename: Andrew
authors.initials: A
authors.lastname: Armstrong
authors.affiliation: Thomas Jefferson University, Philadelphia, PA, United States.
authors.forename: Wm Kevin
authors.initials: WK
authors.lastname: Kelly
authors.affiliation: New York University Clinical Cancer Center, New York, NY, United States.
authors.forename: Anna
authors.initials: A
authors.lastname: Ferrari
authors.affiliation: Sarah Cannon Research Institute, Nashville, TN, United States.
authors.forename: John
authors.initials: J
authors.lastname: Hainsworth
authors.affiliation: Eli Lilly and Company, Bridgewater, NJ, United States.
authors.forename: Adarsh
authors.initials: A
authors.lastname: Joshi
authors.affiliation: Eli Lilly and Company, Indianapolis, IN, United States.
authors.forename: Rebecca R
authors.initials: RR
authors.lastname: Hozak
authors.affiliation: Eli Lilly and Company, Bridgewater, NJ, United States.
authors.forename: Ling
authors.initials: L
authors.lastname: Yang
authors.affiliation: Eli Lilly and Company, Bridgewater, NJ, United States.
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Schwartz
authors.affiliation: University of Washington, Fred Hutchinson Cancer Research Center, Seattle, WA, United States.
authors.forename: Celestia S
authors.initials: CS
authors.lastname: Higano
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000401:mortality / Q000556:secondary; D000293:Adolescent; D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D018450:Disease Progression; D018572:Disease-Free Survival; D000077143:Docetaxel; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D008942:Mitoxantrone / Q000008:administration & dosage; D011241:Prednisone / Q000008:administration & dosage; D016016:Proportional Hazards Models; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D043823:Taxoids / Q000627:therapeutic use*; D013997:Time Factors; D016896:Treatment Outcome; D014481:United States; D055815:Young Adult; D000096662:Ramucirumab
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000077143:Docetaxel; D008942:Mitoxantrone; D011241:Prednisone; D043823:Taxoids; D000096662:Ramucirumab; C557414:cixutumumab
keywords: Cixutumumab; Mitoxantrone; Prednisone; Prostate cancer; Ramucirumab