A phase I trial of escalating doses of the anti-IGF-1R monoclonal antibody (mAb) cixutumumab (IMC-A12) and sorafenib for treatment of advanced hepatocellular carcinoma (HCC).

Abstract

TPS212 Background: This phase I study of cixutumumab and sorafenib in HCC patients is being conducted through a co-operative agreement between the California Cancer Consortium and the NCI. Sorafenib is the only approved drug for advanced HCC; median survival in the SHARP trial was nearly 3 months longer for sorafenib-treated HCC patients than controls. Cixutumumab (ImClone Systems) is a fully human IgG1 mAb that blocks the interaction of Type I Insulin-Like Growth Factor Receptor (IGF-1R) with its ligands (IGF-1 and IGF-II), and induces internalization and degradation of IGF-1R. Cixutumumab inhibits tumor growth in a wide range of human cancer models as a single agent and when combined with chemotherapy, or molecularly targeted agents. An initial study showed that cixutumumab was well tolerated at doses up to 10 mg/kg/week; the most prevalent adverse event was hyperglycemia. Preclinical experiments using in vivo HCC models showed activated IGF signaling and antitumor effects due to cixutumumab. Given the cross-talk between the IGF and VEGF pathways, the combination of cixutumumab and sorafenib was chosen for study. Methods: Study objectives are to: 1) establish the MTD of the sorafenib/cixutumumab combination in patients with advanced HCC; 2) evaluate toxicity; 3) determine the impact of cixutumumab on the IGF-1R/IGF pathway; and 4) obtain preliminary efficacy data. All patients in three cixutumumab dose escalation groups (2, 4, or 6 mg/kg/week) will also be treated with sorafenib (400 mg twice daily). Additional patients will be treated at the MTD. Correlative studies will be performed on 24 patients at the MTD: tumor IGF-1R expression and gene copy number by silver in situ hybridization (SISH), plasma IGF-1R ligands and binding protein levels, hepatocyte growth factor, and c-Met phosphorylation. Eligibility criteria include: unresectable HCC; no prior systemic therapy, ECOG 0 or 1, platelets > 75,000/mm3; albumin > 2.8 g/dl; and Child-Pugh cirrhosis A or B (up to 7 points). Two patients have been accrued to the study thus far. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Response Genetics Amgen, AstraZeneca, Biodesix, Boehringer Ingelheim, Bristol-Myers Squibb, Genentech, GlaxoSmithKline, ImClone Systems, Lilly, Merck, Novartis, Pfizer, sanofi-aventis Bayer Abbott Laboratories, Bayer/Onyx, Bristol-Myers Squibb, Genentech, ImClone Systems, Lilly, Merck, Novartis, Pfizer