title: A phase I trial of vertical inhibition of IGF signalling using cixutumumab, an anti-IGF-1R antibody, and selumetinib, an MEK 1/2 inhibitor, in advanced solid tumours.
abstract: BACKGROUND
  We completed a phase I clinical trial to test the safety and toxicity of combined treatment with cixutumumab (anti-IGF-1R antibody) and selumetinib (MEK 1/2 inhibitor).
  
  
  METHODS
  Patients with advanced solid tumours, refractory to standard therapy received selumetinib hydrogen sulphate capsules orally twice daily, and cixutumumab intravenously on days 1 and 15 of each 28-day cycle. The study used a 3+3 design, with a dose-finding cohort followed by an expansion cohort at the maximally tolerated dose that included pharmacokinetic and pharmacodynamic correlative studies.
  
  
  RESULTS
  Thirty patients were enrolled, with 16 in the dose-finding cohort and 14 in the expansion cohort. Grade 3 or greater toxicities included nausea and vomiting, anaemia, CVA, hypertension, hyperglycaemia, and ophthalmic symptoms. The maximally tolerated combination dose was 50 mg twice daily of selumetinib and 12 mg kg(-1) every 2 weeks of cixutumumab. Two patients achieved a partial response (one unconfirmed), including a patient with BRAF wild-type thyroid carcinoma, and a patient with squamous cell carcinoma of the tongue, and six patients achieved time to progression of >6 months, including patients with thyroid carcinoma, colorectal carcinoma, and basal cell carcinoma. Comparison of pre- and on-treatment biopsies showed significant suppression of pERK and pS6 activity with treatment.
  
  
  CONCLUSIONS
  Our study of anti-IGF-1R antibody cixutumumab and MEK 1/2 inhibitor selumetinib showed that the combination is safe and well-tolerated at these doses, with preliminary evidence of clinical benefit and pharmacodynamic evidence of target inhibition.
authors.affiliation: Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at The Johns Hopkins University School of Medicine, 1650 Orleans Street, Baltimore, MD 21231, USA.
authors.forename: B A
authors.initials: BA
authors.lastname: Wilky
authors.affiliation: Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at The Johns Hopkins University School of Medicine, 1650 Orleans Street, Baltimore, MD 21231, USA.
authors.forename: M A
authors.initials: MA
authors.lastname: Rudek
authors.affiliation: Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at The Johns Hopkins University School of Medicine, 1650 Orleans Street, Baltimore, MD 21231, USA.
authors.forename: S
authors.initials: S
authors.lastname: Ahmed
authors.affiliation: Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at The Johns Hopkins University School of Medicine, 1650 Orleans Street, Baltimore, MD 21231, USA.
authors.forename: D A
authors.initials: DA
authors.lastname: Laheru
authors.affiliation: Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at The Johns Hopkins University School of Medicine, 1650 Orleans Street, Baltimore, MD 21231, USA.
authors.forename: D
authors.initials: D
authors.lastname: Cosgrove
authors.affiliation: Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at The Johns Hopkins University School of Medicine, 1650 Orleans Street, Baltimore, MD 21231, USA.
authors.forename: R C
authors.initials: RC
authors.lastname: Donehower
authors.affiliation: Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at The Johns Hopkins University School of Medicine, 1650 Orleans Street, Baltimore, MD 21231, USA.
authors.forename: B
authors.initials: B
authors.lastname: Nelkin
authors.affiliation: Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at The Johns Hopkins University School of Medicine, 1650 Orleans Street, Baltimore, MD 21231, USA.
authors.forename: D
authors.initials: D
authors.lastname: Ball
authors.affiliation: National Cancer Institute, 9609 Medical Center Drive, MSC 9379, Bethesda, MD 20892, USA.
authors.forename: L A
authors.initials: LA
authors.lastname: Doyle
authors.affiliation: National Cancer Institute, 9609 Medical Center Drive, MSC 9379, Bethesda, MD 20892, USA.
authors.forename: H
authors.initials: H
authors.lastname: Chen
authors.affiliation: Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at The Johns Hopkins University School of Medicine, 1650 Orleans Street, Baltimore, MD 21231, USA.
authors.forename: X
authors.initials: X
authors.lastname: Ye
authors.affiliation: Oncology iMed, AstraZeneca, Mereside, Alderley Park, Maccelsfield, Cheshire SK104TG, UK.
authors.forename: G
authors.initials: G
authors.lastname: Bigley
authors.affiliation: Oncology iMed, AstraZeneca, Mereside, Alderley Park, Maccelsfield, Cheshire SK104TG, UK.
authors.forename: C
authors.initials: C
authors.lastname: Womack
authors.affiliation: Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at The Johns Hopkins University School of Medicine, 1650 Orleans Street, Baltimore, MD 21231, USA.
authors.forename: N S
authors.initials: NS
authors.lastname: Azad
mesh_terms: D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001562:Benzimidazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D015331:Cohort Studies; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors; D016896:Treatment Outcome
chemical_list: C517975:AZD 6244; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D001562:Benzimidazoles; C557414:cixutumumab; D017526:Receptor, IGF Type 1; D020930:MAP Kinase Kinase Kinases