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 67.5 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.
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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