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 B Benson III, Yingjun Su, Linda Horton, Sarah P. Short, John Sae Wook Kauh, Charles Staley, Mary Frances Mulcahy, Mark Powell, Katayoun I. Amiri, Ann Richmond, Jordan Berlin

*Corresponding author for this work

Research output: Contribution to journalArticle

12 Citations (Scopus)

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 - Jan 1 2014

Fingerprint

Doxorubicin
Hepatocellular Carcinoma
Proteasome Endopeptidase Complex
Interleukin-8
Embolism and Thrombosis
Chemokine CCL5
Glucose Intolerance
Therapeutics
Bortezomib
Ascites
Hyperglycemia
Vascular Endothelial Growth Factor A
Multicenter Studies
Interleukin-6
Research Design
Hypertension
Survival
Serum
Neoplasms

Keywords

  • Bortezomib
  • Doxorubicin
  • Hepatocellular carcinoma
  • Proteasome inhibition

ASJC Scopus subject areas

  • Oncology
  • Pharmacology
  • Pharmacology (medical)

Cite this

Ciombor, Kristen K. ; Feng, Yang ; Benson III, Al B ; Su, Yingjun ; Horton, Linda ; Short, Sarah P. ; Kauh, John Sae Wook ; Staley, Charles ; Mulcahy, Mary Frances ; Powell, Mark ; Amiri, Katayoun I. ; Richmond, Ann ; Berlin, Jordan. / Phase II trial of bortezomib plus doxorubicin in hepatocellular carcinoma (E6202) : A trial of the Eastern Cooperative Oncology Group. In: Investigational New Drugs. 2014 ; Vol. 32, No. 5. pp. 1017-1027.
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title = "Phase II trial of bortezomib plus doxorubicin in hepatocellular carcinoma (E6202): A trial of the Eastern Cooperative Oncology Group",
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.",
keywords = "Bortezomib, Doxorubicin, Hepatocellular carcinoma, Proteasome inhibition",
author = "Ciombor, {Kristen K.} and Yang Feng and {Benson III}, {Al B} and Yingjun Su and Linda Horton and Short, {Sarah P.} and Kauh, {John Sae Wook} and Charles Staley and Mulcahy, {Mary Frances} and Mark Powell and Amiri, {Katayoun I.} and Ann Richmond and Jordan Berlin",
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Ciombor, KK, Feng, Y, Benson III, AB, Su, Y, Horton, L, Short, SP, Kauh, JSW, Staley, C, Mulcahy, MF, Powell, M, Amiri, KI, 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, vol. 32, no. 5, pp. 1017-1027. https://doi.org/10.1007/s10637-014-0111-8

Phase II trial of bortezomib plus doxorubicin in hepatocellular carcinoma (E6202) : A trial of the Eastern Cooperative Oncology Group. / Ciombor, Kristen K.; Feng, Yang; Benson III, Al B; Su, Yingjun; Horton, Linda; Short, Sarah P.; Kauh, John Sae Wook; Staley, Charles; Mulcahy, Mary Frances; Powell, Mark; Amiri, Katayoun I.; Richmond, Ann; Berlin, Jordan.

In: Investigational New Drugs, Vol. 32, No. 5, 01.01.2014, p. 1017-1027.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Phase II trial of bortezomib plus doxorubicin in hepatocellular carcinoma (E6202)

T2 - A trial of the Eastern Cooperative Oncology Group

AU - Ciombor, Kristen K.

AU - Feng, Yang

AU - Benson III, Al B

AU - Su, Yingjun

AU - Horton, Linda

AU - Short, Sarah P.

AU - Kauh, John Sae Wook

AU - Staley, Charles

AU - Mulcahy, Mary Frances

AU - Powell, Mark

AU - Amiri, Katayoun I.

AU - Richmond, Ann

AU - Berlin, Jordan

PY - 2014/1/1

Y1 - 2014/1/1

N2 - 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.

AB - 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.

KW - Bortezomib

KW - Doxorubicin

KW - Hepatocellular carcinoma

KW - Proteasome inhibition

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