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

Ciombor KK, Feng Y, Benson AB, Su Y, Horton L, Short SP, Kauh JS, Staley C, Mulcahy M, Powell M, Amiri KI, Richmond A, Berlin J
Invest New Drugs. 2014 32 (5): 1017-27

PMID: 24890858 · PMCID: PMC4171216 · DOI:10.1007/s10637-014-0111-8

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/m(2) IV on d1, 4, 8, 11) and doxorubicin (15 mg/m(2) 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 6.1 months. The most 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.

MeSH Terms (19)

Adult Aged Antineoplastic Combined Chemotherapy Protocols Boronic Acids Bortezomib Carcinoma, Hepatocellular Chemokine CCL5 Cytokines Disease-Free Survival Doxorubicin Female Humans Liver Neoplasms Male Middle Aged Pyrazines Treatment Outcome Vascular Endothelial Growth Factor A Young Adult

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