January 20, 2014

J Hepatol. 2014 Feb;60(2):319-24. doi: 10.1016/j.jhep.2013.09.008. Epub 2013 Sep 14.

Abou-Alfa GK1, Capanu M2, O'Reilly EM3, Ma J4, Chou JF2, Gansukh B4, Shia J5, Kalin M4, Katz S6, Abad L7, Reidy-Lagunes DL3, Kelsen DP3, Chen HX8, Saltz LB3.

BACKGROUND & AIMS: 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 67.5years (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 8months (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.

Copyright © 2013 European Association for the Study of the Liver. All rights reserved.

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

PMID: 24045151 [PubMed - in process]

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