title: TRAIL receptor agonist conatumumab with modified FOLFOX6 plus bevacizumab for first-line treatment of metastatic colorectal cancer: A randomized phase 1b/2 trial.
abstract: BACKGROUND
  In patients with previously untreated metastatic colorectal cancer (mCRC), we conducted a phase 1b/randomized phase 2 trial to define the safety, tolerability, and efficacy of mFOLFOX6 plus bevacizumab (mFOLFOX6/bev) with conatumumab, an investigational, fully human monoclonal IgG1 antibody that specifically activates death receptor 5 (DR5).
  
  
  METHODS
  Twelve patients were enrolled in a phase 1b open-label dose-escalation trial of conatumumab with mFOLFOX6/bev; thereafter, 190 patients were randomized 1:1:1 to receive mFOLFOX6/bev in combination with 2 mg/kg conatumumab, 10 mg/kg conatumumab, or placebo. Therapy cycles were repeated every 2 weeks until disease progression or the occurrence of unacceptable toxicity.
  
  
  RESULTS
  In phase 1b, conatumumab with mFOLFOX6/bev was tolerated without apparent added toxicity over mFOLFOX6/bev alone. In phase 2, conatumumab with mFOLFOX6/bev did not confer a benefit in progression-free survival when compared with placebo with mFOLFOX6/bev. Toxicity was similar in all treatment arms. Following treatment, similar increases in circulating caspase-3 levels were observed in all arms.
  
  
  CONCLUSIONS
  Conatumumab with mFOLFOX6/bev did not offer improved efficacy over the same chemotherapy with placebo in first-line treatment of patients with mCRC. These data do not support further development of conatumumab in advanced CRC.
authors.affiliation: Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Charles S
authors.initials: CS
authors.lastname: Fuchs
authors.forename: Marwan
authors.initials: M
authors.lastname: Fakih
authors.forename: Lee
authors.initials: L
authors.lastname: Schwartzberg
authors.forename: Allen L
authors.initials: AL
authors.lastname: Cohn
authors.forename: Lorrin
authors.initials: L
authors.lastname: Yee
authors.forename: Luke
authors.initials: L
authors.lastname: Dreisbach
authors.forename: Mark F
authors.initials: MF
authors.lastname: Kozloff
authors.forename: Yong-jiang
authors.initials: YJ
authors.lastname: Hei
authors.forename: Francesco
authors.initials: F
authors.lastname: Galimi
authors.forename: Yang
authors.initials: Y
authors.lastname: Pan
authors.forename: Vincent
authors.initials: V
authors.lastname: Haddad
authors.forename: Cheng-Pang
authors.initials: CP
authors.lastname: Hsu
authors.forename: Antony
authors.initials: A
authors.lastname: Sabin
authors.forename: Leonard
authors.initials: L
authors.lastname: Saltz
mesh_terms: D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000009:adverse effects; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000068258:Bevacizumab; D014408:Biomarkers, Tumor / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D018450:Disease Progression; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects; D006801:Humans; D002955:Leucovorin / Q000008:administration & dosage / Q000009:adverse effects; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009944:Organoplatinum Compounds / Q000008:administration & dosage / Q000009:adverse effects; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000819:agonists* / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D014408:Biomarkers, Tumor; D009944:Organoplatinum Compounds; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; C554537:conatumumab; D000068258:Bevacizumab; D053148:Caspase 3; D002955:Leucovorin; D005472:Fluorouracil
keywords: AMG 655; FOLFOX; bevacizumab; conatumumab; death receptor 5 agonist; metastatic colorectal cancer