title: Randomized phase II study of modified FOLFOX-6 in combination with ramucirumab or icrucumab as second-line therapy in patients with metastatic colorectal cancer after disease progression on first-line irinotecan-based therapy.
abstract: Icrucumab and ramucirumab are recombinant human IgG1 monoclonal antibodies that bind VEGF receptors 1 and 2 (VEGFR-1 and -2), respectively. This randomized phase II study evaluated the antitumor activity and safety of icrucumab and ramucirumab each in combination with mFOLFOX-6 in patients with metastatic colorectal cancer after disease progression on first-line therapy with a fluoropyrimidine and irinotecan.
  
  
  
  Eligible patients were randomly assigned to receive mFOLFOX-6 alone (mFOLFOX-6) or in combination with ramucirumab 8 mg/kg IV (RAM+mFOLFOX-6) or icrucumab 15 mg/kg IV (ICR+mFOLFOX-6) every 2 weeks. Randomization was stratified by prior bevacizumab therapy. The primary end point was progression-free survival (PFS). Secondary end points included overall survival (OS), tumor response, safety, and PK.
  
  
  
  In total, 158 patients were randomized, but only 153 received treatment (49 on mFOLFOX-6, 52 on RAM+mFOLFOX-6, and 52 on ICR+mFOLFOX-6). Median PFS was 18.4 weeks on mFOLFOX-6, 21.4 weeks on RAM+mFOLFOX-6, and 15.9 weeks on ICR+mFOLFOX-6 (RAM+mFOLFOX-6 versus mFOLFOX-6, stratified hazard ratio [HR] 1.116 [95% CI 0.713-1.745], P = 0.623; ICR+mFOLFOX-6 versus mFOLFOX-6, stratified HR 1.603 [95% CI 1.011-2.543], P = 0.044). Median survival was 53.6 weeks on mFOLFOX-6, 41.7 weeks on RAM+mFOLFOX-6, and 42.0 weeks on ICR+mFOLFOX-6. The most frequent adverse events reported on the ramucirumab arm (RAM+mFOLFOX-6) were fatigue, nausea, and peripheral sensory neuropathy; those on the icrucumab arm (ICR+mFOLFOX-6) were fatigue, diarrhea, and peripheral sensory neuropathy. Grade ≥3 serious adverse events occurred at comparable frequency across arms.
  
  
  
  In this study population, combining ramucirumab or icrucumab with mFOLFOX-6 did not achieve the predetermined improvement in PFS.
  
  
  
  NCT01111604.
authors.affiliation: British Columbia Cancer Agency, Vancouver Cancer Centre, Vancouver malcolm.moore@bccancer.bc.ca.
authors.forename: M
authors.initials: M
authors.lastname: Moore
authors.affiliation: British Columbia Cancer Agency, Vancouver Cancer Centre, Vancouver.
authors.forename: S
authors.initials: S
authors.lastname: Gill
authors.affiliation: The Ottawa Hospital Cancer Centre, Ottawa.
authors.forename: T
authors.initials: T
authors.lastname: Asmis
authors.affiliation: Sunnybrook Odette Cancer Centre, Toronto.
authors.forename: S
authors.initials: S
authors.lastname: Berry
authors.affiliation: Mount Sinai Hospital, Toronto.
authors.forename: R
authors.initials: R
authors.lastname: Burkes
authors.affiliation: Juravinski Cancer Centre, Hamilton Health Sciences, Hamilton.
authors.forename: K
authors.initials: K
authors.lastname: Zbuk
authors.affiliation: Department of Oncology, McGill University, Montréal.
authors.forename: T
authors.initials: T
authors.lastname: Alcindor
authors.affiliation: Atlantic Clinical Cancer Research Unit, QEII Health Sciences Centre, Nova Scotia Cancer Centre, Halifax.
authors.forename: A
authors.initials: A
authors.lastname: Jeyakumar
authors.affiliation: Fraser Valley Cancer Centre, British Columbia Cancer Agency, Surrey.
authors.forename: T
authors.initials: T
authors.lastname: Chan
authors.affiliation: Kelowna Cancer Centre, British Columbia Cancer Agency, Kelowna.
authors.forename: S
authors.initials: S
authors.lastname: Rao
authors.affiliation: Cross Cancer Institute, Edmonton.
authors.forename: J
authors.initials: J
authors.lastname: Spratlin
authors.affiliation: Tom Baker Cancer Centre, Calgary.
authors.forename: P A
authors.initials: PA
authors.lastname: Tang
authors.affiliation: RSM Durham Regional Cancer Centre, Lakeridge Health Oshawa, Oshawa, Canada.
authors.forename: J
authors.initials: J
authors.lastname: Rothenstein
authors.affiliation: Vanderbilt-Ingram Cancer Center, Nashville.
authors.forename: E
authors.initials: E
authors.lastname: Chan
authors.affiliation: Sarah Cannon Research Institute/Tennessee Oncology, Nashville.
authors.forename: J
authors.initials: J
authors.lastname: Bendell
authors.affiliation: South Carolina Oncology Associates, Sarah Cannon Research Institute, Columbia.
authors.forename: F
authors.initials: F
authors.lastname: Kudrik
authors.affiliation: Eli Lilly and Company, Indianapolis, USA.
authors.forename: J
authors.initials: J
authors.lastname: Kauh
authors.affiliation: Eli Lilly and Company, Indianapolis, USA.
authors.forename: S
authors.initials: S
authors.lastname: Tang
authors.affiliation: Eli Lilly and Company, Indianapolis, USA.
authors.forename: L
authors.initials: L
authors.lastname: Gao
authors.affiliation: Eli Lilly and Company, Indianapolis, USA.
authors.forename: S R P
authors.initials: SR
authors.lastname: Kambhampati
authors.affiliation: Eli Lilly and Company, Indianapolis, USA.
authors.forename: F
authors.initials: F
authors.lastname: Nasroulah
authors.affiliation: Eli Lilly and Company, Indianapolis, USA.
authors.forename: L
authors.initials: L
authors.lastname: Yang
authors.affiliation: Eli Lilly and Company, Indianapolis, USA.
authors.forename: N
authors.initials: N
authors.lastname: Ramdas
authors.affiliation: Eli Lilly and Company, Indianapolis, USA.
authors.forename: P
authors.initials: P
authors.lastname: Binder
authors.affiliation: Trillium Health Partners, Mississauga, Canada.
authors.forename: E
authors.initials: E
authors.lastname: Strevel
mesh_terms: D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000009:adverse effects; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects; D002166:Camptothecin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D018450:Disease Progression; D018572:Disease-Free Survival; D064420:Drug-Related Side Effects and Adverse Reactions / Q000145:classification / Q000473:pathology; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects; D006801:Humans; D000077146:Irinotecan; 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; D000096662:Ramucirumab
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D002166:Camptothecin; D005472:Fluorouracil; D000077146:Irinotecan; D002955:Leucovorin; D009944:Organoplatinum Compounds; D000096662:Ramucirumab
keywords: VEGF; colorectal cancer; icrucumab; irinotecan; modified FOLFOX-6; ramucirumab