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

Research output: Contribution to journalArticle

2 Citations (Scopus)

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

Fingerprint

Toxicity
Hepatocellular Carcinoma
Somatomedins
Liver Neoplasms
Peritonitis
Therapeutics
Hypophosphatemia
Somatomedin Receptors
Maximum Tolerated Dose
Hyperglycemia
Vascular Endothelial Growth Factor A
Disease-Free Survival
anti-IGF-1R antibody A12
sorafenib
Monoclonal Antibodies
Survival

Keywords

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

ASJC Scopus subject areas

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

Cite this

A phase I trial of escalating doses of cixutumumab (IMC-A12) and sorafenib in the treatment of advanced hepatocellular carcinoma. / El-Khoueiry, Anthony B.; O’Donnell, Robert; Semrad, Thomas J.; Mack, Philip; Blanchard, Suzette; Bahary, Nathan; Jiang, Yixing; Yen, Yun; Wright, John; Chen, Helen; Lenz, Heinz Josef; Gandara, David R.

In: Cancer Chemotherapy and Pharmacology, Vol. 81, No. 5, 01.05.2018, p. 957-963.

Research output: Contribution to journalArticle

El-Khoueiry, AB, O’Donnell, R, Semrad, TJ, Mack, P, Blanchard, S, Bahary, N, Jiang, Y, Yen, Y, Wright, J, Chen, H, Lenz, HJ & Gandara, DR 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, vol. 81, no. 5, pp. 957-963. https://doi.org/10.1007/s00280-018-3553-4
El-Khoueiry, Anthony B. ; O’Donnell, Robert ; Semrad, Thomas J. ; Mack, Philip ; Blanchard, Suzette ; Bahary, Nathan ; Jiang, Yixing ; Yen, Yun ; Wright, John ; Chen, Helen ; Lenz, Heinz Josef ; Gandara, David R. / A phase I trial of escalating doses of cixutumumab (IMC-A12) and sorafenib in the treatment of advanced hepatocellular carcinoma. In: Cancer Chemotherapy and Pharmacology. 2018 ; Vol. 81, No. 5. pp. 957-963.
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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.",
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AU - Mack, Philip

AU - Blanchard, Suzette

AU - Bahary, Nathan

AU - Jiang, Yixing

AU - Yen, Yun

AU - Wright, John

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AU - Lenz, Heinz Josef

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