title: ICECREAM: randomised phase II study of cetuximab alone or in combination with irinotecan in patients with metastatic colorectal cancer with either KRAS, NRAS, BRAF and PI3KCA wild type, or G13D mutated tumours.
abstract: Patients with metastatic colorectal cancer whose disease has progressed on oxaliplatin- and irinotecan-containing regimens may benefit from EGFR-inhibiting monoclonal antibodies if they do not contain mutations in the KRAS gene (are "wild type"). It is unknown whether these antibodies, such as cetuximab, are more efficacious in refractory metastatic colorectal cancer as monotherapy, or in combination with irinotecan. Lack of mutation in KRAS, BRAF and PIK3CA predicts response to EFGR-inhibitors. The ICECREAM trial examines the question of monotherapy versus combination with chemotherapy in two groups of patients: those with a "quadruple wild type" tumour genotype (no mutations in KRAS, NRAS, PI3KCA or BRAF genes) and those with the specific KRAS mutation in codon G13D, for whom possibly EGFR-inhibitor efficacy may be equivalent.
  
  
  
  ICECREAM is a randomised, phase II, open-label, controlled trial comparing the efficacy of cetuximab alone or with irinotecan in patients with "quadruple wild type" or G13D-mutated metastatic colorectal cancer, whose disease has progressed on, or who are intolerant of oxaliplatin- and fluoropyrimidine-based chemotherapy. The primary endpoint is the 6-month progression-free survival benefit of the treatment regimen. Secondary endpoints are response rate, overall survival, and quality of life. The tertiary endpoint is prediction of outcome with further biological markers. International collaboration has facilitated recruitment in this prospective trial of treatment in these infrequently found molecular subsets of colorectal cancer.
  
  
  
  This unique trial will yield prospective information on the efficacy of cetuximab and whether this is further enhanced with chemotherapy in two distinct populations of patients with metastatic colorectal cancer: the "quadruple wild type", which may 'superselect' for tumours sensitive to EGFR-inhibition, and the rare KRAS G13D mutated tumours, which are also postulated to be sensitive to the drug. The focus on establishing both positive and negative predictive factors for the response to targeted therapy is an attempt to improve outcomes, reduce toxicity and contain treatment costs. Tissue and blood will yield a resource for molecular studies. Recruitment, particularly of patients with the rare G13D mutation, will demonstrate the ability for international collaboration to run prospective trials in small colorectal cancer molecular subgroups.
  
  
  
  Australian and New Zealand Clinical Trials Registry: ACTRN12612000901808 , registered 16 August 2012.
authors.affiliation: St Vincent's Clinical School, University of New South Wales, Sydney, NSW, Australia. e.segelov@unsw.edu.au.
authors.forename: Eva
authors.initials: E
authors.lastname: Segelov
authors.affiliation: University of Melbourne, Melbourne, Australia.
authors.forename: Paul
authors.initials: P
authors.lastname: Waring
authors.affiliation: Royal Melbourne Hospital, Melbourne, Australia.|Peter MacCallum Cancer Centre, Melbourne, Australia.
authors.forename: Jayesh
authors.initials: J
authors.lastname: Desai
authors.affiliation: NHMRC Clinical Trials Centre, University of Sydney, Sydney, Australia.
authors.forename: Kate
authors.initials: K
authors.lastname: Wilson
authors.affiliation: NHMRC Clinical Trials Centre, University of Sydney, Sydney, Australia.
authors.forename: Val
authors.initials: V
authors.lastname: Gebski
authors.affiliation: NHMRC Clinical Trials Centre, University of Sydney, Sydney, Australia.
authors.forename: Subotheni
authors.initials: S
authors.lastname: Thavaneswaran
authors.affiliation: Vall d'Hebron University Hospital, Barcelona, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: Elez
authors.affiliation: Border Medical Oncology, Albury-Wodonga, Australia.
authors.forename: Craig
authors.initials: C
authors.lastname: Underhill
authors.affiliation: Northern Cancer Institute, Royal North Shore Hospital, University of Sydney, Sydney, Australia.
authors.forename: Nick
authors.initials: N
authors.lastname: Pavlakis
authors.affiliation: Macarthur Cancer Therapy Centre, Campbelltown Hospital, Sydney, Australia.|Kinghorn Cancer Centre, Sydney, Australia.
authors.forename: Lorraine
authors.initials: L
authors.lastname: Chantrill
authors.affiliation: Royal Hobart Hospital, Hobart, Australia.
authors.forename: Louise
authors.initials: L
authors.lastname: Nott
authors.affiliation: Peter MacCallum Cancer Centre, Melbourne, Australia.
authors.forename: Michael
authors.initials: M
authors.lastname: Jefford
authors.affiliation: NHMRC Clinical Trials Centre, University of Sydney, Sydney, Australia.|Andrew Love Cancer Centre, Geelong, Australia.
authors.forename: Mustafa
authors.initials: M
authors.lastname: Khasraw
authors.affiliation: Calvary Mater Newcastle, University of Newcastle, Newcastle, Australia.
authors.forename: Fiona
authors.initials: F
authors.lastname: Day
authors.affiliation: Hammersmith Hospital, London, UK.
authors.forename: Harpreet
authors.initials: H
authors.lastname: Wasan
authors.affiliation: Oncologia Medica, Seconda Università degli Studi di Napoli, Naples, Italy.
authors.forename: Fortunato
authors.initials: F
authors.lastname: Ciardiello
authors.affiliation: Flinders Medical Centre, Adelaide, Australia.
authors.forename: Chris
authors.initials: C
authors.lastname: Karapetis
authors.affiliation: Princess Alexandra Hospital, Brisbane, Australia.
authors.forename: Warren
authors.initials: W
authors.lastname: Joubert
authors.affiliation: Sir Charles Gairdner Hospital, Perth, Australia.
authors.forename: Guy
authors.initials: G
authors.lastname: van Hazel
authors.affiliation: Alfred Hospital, Melbourne, Australia.
authors.forename: Andrew
authors.initials: A
authors.lastname: Haydon
authors.affiliation: Queen Elizabeth Hospital, Lyell McEwin Hospital, Adelaide, Australia.
authors.forename: Tim
authors.initials: T
authors.lastname: Price
authors.affiliation: University Hospitals Leuven, Campus Gasthuisberg, Leuven, Belgium.
authors.forename: Sabine
authors.initials: S
authors.lastname: Tejpar
authors.affiliation: Austin Hospital, Melbourne, Australia.
authors.forename: Niall
authors.initials: N
authors.lastname: Tebbutt
authors.affiliation: Cabrini Hospital, Melbourne, Australia.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Shapiro
mesh_terms: D051702:Activating Transcription Factor 6; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D050976:Basic-Leucine Zipper Transcription Factors / Q000235:genetics; D002166:Camptothecin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D000068818:Cetuximab / Q000008:administration & dosage* / Q000009:adverse effects; D058534:Class I Phosphatidylinositol 3-Kinases / Q000235:genetics; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics; D018572:Disease-Free Survival; D020558:GTP Phosphohydrolases / Q000235:genetics; D006801:Humans; D000077146:Irinotecan; D008565:Membrane Proteins / Q000235:genetics; D009154:Mutation; D011446:Prospective Studies; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D012107:Research Design
chemical_list: C487807:ATF6B protein, human; D051702:Activating Transcription Factor 6; D000970:Antineoplastic Agents; D050976:Basic-Leucine Zipper Transcription Factors; C117307:KRAS protein, human; D008565:Membrane Proteins; D000077146:Irinotecan; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras); D000068818:Cetuximab; D002166:Camptothecin
keywords: Cetuximab; Clinical trial; Colorectal tumours; Irinotecan; Tumour mutations