title: A phase II study of cixutumumab (IMC-A12, NSC742460) in advanced hepatocellular carcinoma.
abstract: OBJECTIVE
  IGF-IR is implicated in hepatic carcinogenesis. This and preliminary evidence of biological activity of anti-IGF-1R monoclonal antibody cixutumumab in phase I trials prompted this phase II study.
  
  
  METHODS
  Patients with advanced HCC, Child-Pugh A-B8, received cixutumumab 6mg/kg weekly, in a Simon two-stage design study, with the primary endpoints being 4-month PFS and RECIST-defined response rate. Tissue and circulating markers plus different HCC scoring systems were evaluated for correlation with PFS and OS.
  
  
  RESULTS
  As a result of pre-specified futility criteria, only stage 1 was accrued: N=24: median age 67.5 years (range 49-83), KPS 80% (70-90%), 20 males (83%), 9 stage III (37%)/15 stage IV (63%), 18 Child-Pugh A (75%), 11 HBV (46%)/10 HCV (42%)/11 alcoholic cirrhosis (46%)/2 NASH (8%), 11 (46%) diabetic. Median number of doses: 7 (range 1-140). Grade 3/4 toxicities >10% included: diabetes, elevated liver function tests, hyponatremia, and lymphopenia. Four-month PFS was 30% (95% CI 13-48), and there were no objective responses. Median overall survival was 8 months (95% CI 5.8-14). IGF-R1 staining did not correlate with outcome. Elevated IGFBP-1 correlated with improved PFS (1.2 [95% CI 1-1.4]; p 0.009) and OS (1.2 [95% CI 1.1-1.4]; p 0.003).
  
  
  CONCLUSIONS
  Cixutumumab monotherapy did not have clinically meaningful activity in this unselected HCC population. Grade 3-4 hyperglycemia occurred in 46% of patients. Elevated IGFBP-1 correlated with improved PFS and OS.
authors.affiliation: Department of Internal Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, United States; Department of Internal Medicine, Weill Medical College at Cornell University, New York, NY, United States. Electronic address: abou-alg@mskcc.org.
authors.forename: Ghassan K
authors.initials: GK
authors.lastname: Abou-Alfa
authors.affiliation: Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY, United States.
authors.forename: Marinela
authors.initials: M
authors.lastname: Capanu
authors.affiliation: Department of Internal Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, United States; Department of Internal Medicine, Weill Medical College at Cornell University, New York, NY, United States.
authors.forename: Eileen M
authors.initials: EM
authors.lastname: O'Reilly
authors.affiliation: Department of Internal Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, United States.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Ma
authors.affiliation: Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY, United States.
authors.forename: Joanne F
authors.initials: JF
authors.lastname: Chou
authors.affiliation: Department of Internal Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, United States.
authors.forename: Bolorsukh
authors.initials: B
authors.lastname: Gansukh
authors.affiliation: Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY, United States.
authors.forename: Jinru
authors.initials: J
authors.lastname: Shia
authors.affiliation: Department of Internal Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, United States.
authors.forename: Marcia
authors.initials: M
authors.lastname: Kalin
authors.affiliation: Department of Radiology, Memorial Sloan-Kettering Cancer Center, New York, NY, United States.
authors.forename: Seth
authors.initials: S
authors.lastname: Katz
authors.affiliation: Research Department, ImClone Systems, a wholly-owned subsidiary of Eli Lilly & Company, New York, NY, United States.
authors.forename: Leslie
authors.initials: L
authors.lastname: Abad
authors.affiliation: Department of Internal Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, United States; Department of Internal Medicine, Weill Medical College at Cornell University, New York, NY, United States.
authors.forename: Diane L
authors.initials: DL
authors.lastname: Reidy-Lagunes
authors.affiliation: Department of Internal Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, United States; Department of Internal Medicine, Weill Medical College at Cornell University, New York, NY, United States.
authors.forename: David P
authors.initials: DP
authors.lastname: Kelsen
authors.affiliation: Cancer Therapy Evaluation Program (CTEP), National Cancer Institute, Bethesda, MD, United States.
authors.forename: Helen X
authors.initials: HX
authors.lastname: Chen
authors.affiliation: Department of Internal Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, United States; Department of Internal Medicine, Weill Medical College at Cornell University, New York, NY, United States.
authors.forename: Leonard B
authors.initials: LB
authors.lastname: Saltz
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D014408:Biomarkers, Tumor / Q000097:blood / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000097:blood / Q000473:pathology / Q000628:therapy*; D005260:Female; D006801:Humans; D018970:Insulin-Like Growth Factor Binding Protein 1 / Q000097:blood; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000097:blood; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D007335:Insulin-Like Growth Factor II / Q000378:metabolism; D053208:Kaplan-Meier Estimate; D008113:Liver Neoplasms / Q000097:blood / Q000473:pathology / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D017526:Receptor, IGF Type 1 / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D014408:Biomarkers, Tumor; C032231:IGFBP1 protein, human; C515497:IGFBP3 protein, human; D018970:Insulin-Like Growth Factor Binding Protein 1; D018972:Insulin-Like Growth Factor Binding Protein 3; C557414:cixutumumab; D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II; D017526:Receptor, IGF Type 1
keywords: ADCC; AJCC; ALT; AST; Alanine aminotransferase; American Joint Committee on Cancer; Antibody-dependent complement-mediated cytotoxicity; Aspartate aminotransferase; CALGB; CC1; CDC; CTCAE; CTEP/NCI; Cancer Leukemia Group B; Cancer Therapy Evaluation Program (CTEP)/National Cancer Institute; Cell conditioning 1; Cells per microliter; Cixutumumab (IMC-A12, NSC742460); Common terminology criteria for adverse events; Complement-dependent cytotoxicity; Diabetes; ELISA; Enzyme-linked immunosorbent assay; Free IGF1; HCC; HIV; HR; Hazard ratio; Hepatocellular Carcinoma; Hepatocellular carcinoma; Human immunodeficiency virus; IGF-1; IGF-1R; IGF-2; IGF-2R; IGF-IR; IGF2; IGFBP 1; IGFBP 3; IRB; IgG1; Immunoglobulin 1; Institutional Review Board; Insulin growth factor 1; Insulin growth factor 1 receptor; Insulin growth factor 2; Insulin growth factor 2 receptor; Insulin-like growth factor binding protein 1; Insulin-like growth factor binding protein 3; KPS; Karnofsky performance status; LOH; Loss of heterozygosity; MAP; Milligram/deciliter; Milliliter per minute; Mitogen activated protein; NASH; Non-alcoholic steatohepatitis; OS; Overall urvival; PFS; PT/INR; Prothrombin time/International normalized ratio; RECIST; Response evaluation criteria in solid tumors; Units/Liter; mcl; mg/dl; mg/kg; milligram/kilogram; ml/min; progression free survival; units/L
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