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

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

Medicine, Hematology Oncology Division

Research output: Contribution to journal › Article › peer-review

28 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 language	English (US)
Pages (from-to)	1017-1027
Number of pages	11
Journal	Investigational New Drugs
Volume	32
Issue number	5
DOIs	https://doi.org/10.1007/s10637-014-0111-8
State	Published - Oct 2014

Funding

Acknowledgments This study was conducted by the Eastern Cooperative Oncology Group (Robert L. Comis), and supported in part by Public Health Service Grants CA23318, CA66636, CA21115, CA49957, CA17145, CA116021, CA9060625, an SRCS award from the Department of Veterans Affairs, and from the National Cancer Institute, National Institutes of Health, and the Department of Health and Human Services. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute. Laboratory correlatives were supported by Public Health Service Grant 5R21 CA099269-02 from the National Cancer Institute.

Keywords

Bortezomib
Doxorubicin
Hepatocellular carcinoma
Proteasome inhibition

ASJC Scopus subject areas

Pharmacology (medical)
Oncology
Pharmacology

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10.1007/s10637-014-0111-8

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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

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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, {Al Bowen} and Yingjun Su and Linda Horton and Short, {Sarah P.} and Kauh, {John Sae Wook} and Charles Staley and Mary Mulcahy and Mark Powell and Amiri, {Katayoun I.} and Ann Richmond and Jordan Berlin",

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doi = "10.1007/s10637-014-0111-8",

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Ciombor, KK, Feng, Y, Benson, AB, Su, Y, Horton, L, Short, SP, Kauh, JSW, Staley, C, Mulcahy, M, 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

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, Al Bowen

AU - Su, Yingjun

AU - Horton, Linda

AU - Short, Sarah P.

AU - Kauh, John Sae Wook

AU - Staley, Charles

AU - Mulcahy, Mary

AU - Powell, Mark

AU - Amiri, Katayoun I.

AU - Richmond, Ann

AU - Berlin, Jordan

PY - 2014/10

Y1 - 2014/10

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

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