An international, multicenter phase II trial of bortezomib in patients with hepatocellular carcinoma

George P. Kim, Michelle R. Mahoney, Daniel Szydlo, Tony S K Mok, Robert Marshke, Kyle Holen, Joel Picus, Michael Boyer, Henry Clement Pitot, Joseph Rubin, Philip A. Philip, Anna Nowak, John J. Wright, Charles Erlichman

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Abstract

Background and Rationale Bortezomib (PS- 341, VELCADE®) is a selective inhibitor of the 26S proteasome, an integral component of the ubiquitinproteasome pathway. This phase II study evaluated the activity and tolerability of bortezomib in unresectable hepatocellular carcinoma (HCC) patients. Methods The primary endpoint was confirmed tumor response rate (RR) with secondary endpoints including duration of response, time to disease progression, survival and toxicity. Treatment consisted of bortezomib, 1.3 mg/m 2 IV bolus on days 1, 4, 8, and 11 of each 21-day treatment cycle. Eligibility included: no prior systemic chemotherapy, ECOG PS 0-2, Child-Pugh A or B, preserved hematologic, hepatic and neurologic function; prior liver-directed therapy was permitted. Results Thirty-five patients enrolled and received a median of 2 cycles of treatment (range 1-12). Overall, 24 and 4 patients had a maximum severity of grade 3 and 4 adverse events (AEs), respectively. No treatment related deaths occurred. Only thrombocytopenia (11%) was seen in greater than 10% of patients. One patient achieved a partial response, lasting 13 weeks during treatment and progressed 11.6 months later; two patients received treatment for greater than 6 months. Median time-to-progression was 1.6 months and median survival was 6.0 months. Conclusions This international, multicenter trial evaluated bortezomib as monotherapy in unresectable HCC patients. And, despite the lack of significant activity, this report serves as a baseline clinical experience for the development of future dual biologic approaches including bortezomib.

Original languageEnglish (US)
Pages (from-to)387-394
Number of pages8
JournalInvestigational New Drugs
Volume30
Issue number1
DOIs
StatePublished - Feb 2012

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Hepatocellular Carcinoma
Therapeutics
Survival
Liver
Bortezomib
Thrombocytopenia
Nervous System
Reaction Time
Multicenter Studies
Disease Progression
Drug Therapy
Neoplasms

Keywords

  • Antineoplastic agents
  • Biologic agents
  • Boronic acids
  • Treatment outcome

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Oncology

Cite this

Kim, G. P., Mahoney, M. R., Szydlo, D., Mok, T. S. K., Marshke, R., Holen, K., ... Erlichman, C. (2012). An international, multicenter phase II trial of bortezomib in patients with hepatocellular carcinoma. Investigational New Drugs, 30(1), 387-394. https://doi.org/10.1007/s10637-010-9532-1

An international, multicenter phase II trial of bortezomib in patients with hepatocellular carcinoma. / Kim, George P.; Mahoney, Michelle R.; Szydlo, Daniel; Mok, Tony S K; Marshke, Robert; Holen, Kyle; Picus, Joel; Boyer, Michael; Pitot, Henry Clement; Rubin, Joseph; Philip, Philip A.; Nowak, Anna; Wright, John J.; Erlichman, Charles.

In: Investigational New Drugs, Vol. 30, No. 1, 02.2012, p. 387-394.

Research output: Contribution to journalArticle

Kim, GP, Mahoney, MR, Szydlo, D, Mok, TSK, Marshke, R, Holen, K, Picus, J, Boyer, M, Pitot, HC, Rubin, J, Philip, PA, Nowak, A, Wright, JJ & Erlichman, C 2012, 'An international, multicenter phase II trial of bortezomib in patients with hepatocellular carcinoma', Investigational New Drugs, vol. 30, no. 1, pp. 387-394. https://doi.org/10.1007/s10637-010-9532-1
Kim, George P. ; Mahoney, Michelle R. ; Szydlo, Daniel ; Mok, Tony S K ; Marshke, Robert ; Holen, Kyle ; Picus, Joel ; Boyer, Michael ; Pitot, Henry Clement ; Rubin, Joseph ; Philip, Philip A. ; Nowak, Anna ; Wright, John J. ; Erlichman, Charles. / An international, multicenter phase II trial of bortezomib in patients with hepatocellular carcinoma. In: Investigational New Drugs. 2012 ; Vol. 30, No. 1. pp. 387-394.
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abstract = "Background and Rationale Bortezomib (PS- 341, VELCADE{\circledR}) is a selective inhibitor of the 26S proteasome, an integral component of the ubiquitinproteasome pathway. This phase II study evaluated the activity and tolerability of bortezomib in unresectable hepatocellular carcinoma (HCC) patients. Methods The primary endpoint was confirmed tumor response rate (RR) with secondary endpoints including duration of response, time to disease progression, survival and toxicity. Treatment consisted of bortezomib, 1.3 mg/m 2 IV bolus on days 1, 4, 8, and 11 of each 21-day treatment cycle. Eligibility included: no prior systemic chemotherapy, ECOG PS 0-2, Child-Pugh A or B, preserved hematologic, hepatic and neurologic function; prior liver-directed therapy was permitted. Results Thirty-five patients enrolled and received a median of 2 cycles of treatment (range 1-12). Overall, 24 and 4 patients had a maximum severity of grade 3 and 4 adverse events (AEs), respectively. No treatment related deaths occurred. Only thrombocytopenia (11{\%}) was seen in greater than 10{\%} of patients. One patient achieved a partial response, lasting 13 weeks during treatment and progressed 11.6 months later; two patients received treatment for greater than 6 months. Median time-to-progression was 1.6 months and median survival was 6.0 months. Conclusions This international, multicenter trial evaluated bortezomib as monotherapy in unresectable HCC patients. And, despite the lack of significant activity, this report serves as a baseline clinical experience for the development of future dual biologic approaches including bortezomib.",
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AU - Kim, George P.

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AU - Marshke, Robert

AU - Holen, Kyle

AU - Picus, Joel

AU - Boyer, Michael

AU - Pitot, Henry Clement

AU - Rubin, Joseph

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AU - Nowak, Anna

AU - Wright, John J.

AU - Erlichman, Charles

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N2 - Background and Rationale Bortezomib (PS- 341, VELCADE®) is a selective inhibitor of the 26S proteasome, an integral component of the ubiquitinproteasome pathway. This phase II study evaluated the activity and tolerability of bortezomib in unresectable hepatocellular carcinoma (HCC) patients. Methods The primary endpoint was confirmed tumor response rate (RR) with secondary endpoints including duration of response, time to disease progression, survival and toxicity. Treatment consisted of bortezomib, 1.3 mg/m 2 IV bolus on days 1, 4, 8, and 11 of each 21-day treatment cycle. Eligibility included: no prior systemic chemotherapy, ECOG PS 0-2, Child-Pugh A or B, preserved hematologic, hepatic and neurologic function; prior liver-directed therapy was permitted. Results Thirty-five patients enrolled and received a median of 2 cycles of treatment (range 1-12). Overall, 24 and 4 patients had a maximum severity of grade 3 and 4 adverse events (AEs), respectively. No treatment related deaths occurred. Only thrombocytopenia (11%) was seen in greater than 10% of patients. One patient achieved a partial response, lasting 13 weeks during treatment and progressed 11.6 months later; two patients received treatment for greater than 6 months. Median time-to-progression was 1.6 months and median survival was 6.0 months. Conclusions This international, multicenter trial evaluated bortezomib as monotherapy in unresectable HCC patients. And, despite the lack of significant activity, this report serves as a baseline clinical experience for the development of future dual biologic approaches including bortezomib.

AB - Background and Rationale Bortezomib (PS- 341, VELCADE®) is a selective inhibitor of the 26S proteasome, an integral component of the ubiquitinproteasome pathway. This phase II study evaluated the activity and tolerability of bortezomib in unresectable hepatocellular carcinoma (HCC) patients. Methods The primary endpoint was confirmed tumor response rate (RR) with secondary endpoints including duration of response, time to disease progression, survival and toxicity. Treatment consisted of bortezomib, 1.3 mg/m 2 IV bolus on days 1, 4, 8, and 11 of each 21-day treatment cycle. Eligibility included: no prior systemic chemotherapy, ECOG PS 0-2, Child-Pugh A or B, preserved hematologic, hepatic and neurologic function; prior liver-directed therapy was permitted. Results Thirty-five patients enrolled and received a median of 2 cycles of treatment (range 1-12). Overall, 24 and 4 patients had a maximum severity of grade 3 and 4 adverse events (AEs), respectively. No treatment related deaths occurred. Only thrombocytopenia (11%) was seen in greater than 10% of patients. One patient achieved a partial response, lasting 13 weeks during treatment and progressed 11.6 months later; two patients received treatment for greater than 6 months. Median time-to-progression was 1.6 months and median survival was 6.0 months. Conclusions This international, multicenter trial evaluated bortezomib as monotherapy in unresectable HCC patients. And, despite the lack of significant activity, this report serves as a baseline clinical experience for the development of future dual biologic approaches including bortezomib.

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KW - Treatment outcome

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