A phase I trial of escalating doses of cixutumumab (IMC-A12) and sorafenib in the treatment of advanced hepatocellular carcinoma

Cancer Chemother Pharmacol. 2018 May;81(5):957-963. doi: 10.1007/s00280-018-3553-4. Epub 2018 Mar 8.


Purpose: The insulin-like growth factor (IGF) pathway is activated in hepatocarcinogenesis. Cixutumumab is a monoclonal antibody against human insulin-like growth factor-1 receptor (IGF-1R). Given the cross-talk between the IGF and VEGF pathways, we performed a phase I study of the combination of cixutumumab and sorafenib in hepatocellular cancer (HCC).

Methods: Eligible patients with no prior systemic therapy for advanced HCC and Child-Pugh A to B7 were treated with sorafenib 400 mg BID and escalating doses of cixutumumab (2, 4, or 6 mg/kg IV weekly) in a 3 + 3 design. Dose limiting toxicity (DLT) was defined as treatment-related grade 3 or 4 non-hematologic toxicity (except for a subset of manageable toxicities) or any grade 4 hematologic toxicities.

Results: In 21 patients enrolled, there were 3 DLTs; grade 3 hyperglycemia, grade 3 hypophosphatemia, and grade 5 peritonitis. The maximum tolerated dose of cixutumumab was 4 mg/kg IV weekly with standard dose sorafenib. Eighteen of 21 (86%) patients had grade 3 or above toxicities attributed to treatment. One patient also experienced grade 4 colonic perforation and grade 5 peritonitis. The median number of cycles completed was 4 (0-26). Of 16 patients evaluable for response, 81% achieved stable disease. The median progression free survival was 6.0 months (95% CI 3.6-undefined) and the median overall survival was 10.5 months (95% CI 7.1-undefined).

Conclusions: While the combination of cixutumumab and sorafenib had a toxicity profile similar to that of sorafenib monotherapy, it manifested limited clinical efficacy in unselected patients with HCC.

Keywords: Cixutumumab; Hepatocellular cancer; IMC-A12; Phase I; Sorafenib.

Publication types

  • Clinical Trial, Phase I
  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Antibodies, Monoclonal / administration & dosage*
  • Antibodies, Monoclonal / adverse effects
  • Antibodies, Monoclonal, Humanized
  • Antineoplastic Combined Chemotherapy Protocols / administration & dosage*
  • Antineoplastic Combined Chemotherapy Protocols / adverse effects
  • Carcinoma, Hepatocellular / drug therapy*
  • Carcinoma, Hepatocellular / mortality
  • Carcinoma, Hepatocellular / pathology
  • Dose-Response Relationship, Drug
  • Feasibility Studies
  • Female
  • Humans
  • Liver Neoplasms / drug therapy*
  • Liver Neoplasms / mortality
  • Liver Neoplasms / pathology
  • Male
  • Maximum Tolerated Dose
  • Middle Aged
  • Progression-Free Survival
  • Sorafenib / administration & dosage*
  • Sorafenib / adverse effects


  • Antibodies, Monoclonal
  • Antibodies, Monoclonal, Humanized
  • cixutumumab
  • Sorafenib