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

Anthony B. El-Khoueiry, Robert O’Donnell, Thomas J. Semrad, Philip Mack, Suzette Blanchard, Nathan Bahary, Yixing Jiang, Yun Yen, John Wright, Helen Chen, Heinz Josef Lenz, David R. Gandara

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Abstract

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.

Original languageEnglish
Pages (from-to)957-963
Number of pages7
JournalCancer Chemotherapy and Pharmacology
Volume81
Issue number5
DOIs
Publication statusPublished - May 1 2018
Externally publishedYes

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Keywords

  • Cixutumumab
  • Hepatocellular cancer
  • IMC-A12
  • Phase I
  • Sorafenib

ASJC Scopus subject areas

  • Oncology
  • Toxicology
  • Pharmacology
  • Cancer Research
  • Pharmacology (medical)

Cite this

El-Khoueiry, A. B., O’Donnell, R., Semrad, T. J., Mack, P., Blanchard, S., Bahary, N., Jiang, Y., Yen, Y., Wright, J., Chen, H., Lenz, H. J., & Gandara, D. R. (2018). A phase I trial of escalating doses of cixutumumab (IMC-A12) and sorafenib in the treatment of advanced hepatocellular carcinoma. Cancer Chemotherapy and Pharmacology, 81(5), 957-963. https://doi.org/10.1007/s00280-018-3553-4