Phase II trial of bortezomib plus doxorubicin in hepatocellular carcinoma (E6202): A trial of the Eastern Cooperative Oncology Group

Kristen K. Ciombor*, Yang Feng, Al Bowen Benson, Yingjun Su, Linda Horton, Sarah P. Short, John Sae Wook Kauh, Charles Staley, Mary Mulcahy, Mark Powell, Katayoun I. Amiri, Ann Richmond, Jordan Berlin

*Corresponding author for this work

Research output: Contribution to journalArticle

16 Scopus citations

Abstract

Purpose: To evaluate the efficacy and tolerability of bortezomib in combination with doxorubicin in patients with advanced hepatocellular carcinoma, and to correlate pharmacodynamic markers of proteasome inhibition with response and survival. Experimental Design: This phase II, open-label, multicenter study examined the efficacy of bortezomib (1.3 mg/m2 IV on d1, 4, 8, 11) and doxorubicin (15 mg/m2 IV on d1, 8) in 21-day cycles. The primary endpoint was objective response rate. Results: Best responses in 38 treated patients were 1 partial response (2.6 %), 10 (26.3 %) stable disease, and 17 (44.7 %) progressive disease; 10 patients were unevaluable. Median PFS was 2.2 months. Median OS was 6.1months. Themost common grade 3 to 4 toxicities were hypertension, glucose intolerance, ascites, ALT elevation, hyperglycemia and thrombosis/embolism. Worse PFS was seen in patients with elevated IL-6, IL-8, MIP-1α and EMSA for NF-κB at the start of treatment. Worse OS was seen in patients with elevated IL-8 and VEGF at the start of treatment. Patients had improved OS if a change in the natural log of serum MIP-1α/CCL3 was seen after treatment. RANTES/CCL5 levels decreased significantly with treatment. Conclusions: The combination of doxorubicin and bortezomib was well-tolerated in patients with hepatocellular carcinoma, but the primary endpoint was not met. Exploratory analyses of markers of proteasome inhibition suggest a possible prognostic and predictive role and should be explored further in tumor types for which bortezomib is efficacious.

Original languageEnglish (US)
Pages (from-to)1017-1027
Number of pages11
JournalInvestigational New Drugs
Volume32
Issue number5
DOIs
StatePublished - Oct 2014

Keywords

  • Bortezomib
  • Doxorubicin
  • Hepatocellular carcinoma
  • Proteasome inhibition

ASJC Scopus subject areas

  • Oncology
  • Pharmacology
  • Pharmacology (medical)

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    Ciombor, K. K., Feng, Y., Benson, A. B., Su, Y., Horton, L., Short, S. P., Kauh, J. S. W., Staley, C., Mulcahy, M., Powell, M., Amiri, K. I., Richmond, A., & Berlin, J. (2014). Phase II trial of bortezomib plus doxorubicin in hepatocellular carcinoma (E6202): A trial of the Eastern Cooperative Oncology Group. Investigational New Drugs, 32(5), 1017-1027. https://doi.org/10.1007/s10637-014-0111-8