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

doi:10.1007/s10637-014-0111-8

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

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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, …

Investigational new drugs, Vol.32(5), pp.1017-1027

10/01/2014

DOI: 10.1007/s10637-014-0111-8

PMCID: PMC4171216

PMID: 24890858

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https://www.ncbi.nlm.nih.gov/pmc/articles/4171216View

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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/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-1 alpha and EMSA for NF-kappa B 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-1 alpha/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.

Life Sciences & Biomedicine

Oncology

Pharmacology & Pharmacy

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Title: Subtitle: Phase II trial of bortezomib plus doxorubicin in hepatocellular carcinoma (E6202): a trial of the Eastern Cooperative Oncology Group
Creators: Kristen K. Ciombor - The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
Yang Feng - Dana-Farber Cancer Institute
Al Bowen Benson - Northwestern University
Yingjun Su - Air Force Medical University
Linda Horton - Vanderbilt University
Sarah P. Short - Vanderbilt University
John Sae Wook Kauh - Emory University
Charles Staley - Emory University
Mary Mulcahy - Northwestern University
Mark Powell - New York Proton Center
Katayoun I. Amiri - Summit (United Kingdom)
Ann Richmond - Vanderbilt University
Jordan Berlin - Vanderbilt University
Resource Type: Journal article
Publication Details: Investigational new drugs, Vol.32(5), pp.1017-1027
DOI: 10.1007/s10637-014-0111-8
PMID: 24890858
PMCID: PMC4171216
NLM abbreviation: Invest New Drugs
ISSN: 0167-6997
eISSN: 1573-0646
Publisher: Springer Nature
Number of pages: 11
Grant note: Department of Health and Human Services U24CA114737 / NATIONAL CANCER INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) CA23318; CA66636; CA21115; CA49957; CA17145; CA116021; CA9060625 / Public Health Service; United States Department of Health & Human Services; United States Public Health Service 5R21 CA099269-02 / Public Health Service from the National Cancer Institute National Cancer Institute, National Institutes of Health; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) SRCS award from the Department of Veterans Affairs P30DK058404 / NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK)
Language: English
Date published: 10/01/2014
Academic Unit: Hematology, Oncology, and Blood & Marrow Transplantation; Internal Medicine
Record Identifier: 9984420846002771

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