Phase II trial of vorinostat in combination with bortezomib in recurrent glioblastoma

A north central cancer treatment group study

Bret B. Friday, S. Keith Anderson, Jan Buckner, Chunrong Yu, Caterina Giannini, Francois Geoffroy, John Schwerkoske, Miroslaw Mazurczak, Howard Gross, Eduardo Pajon, Kurt Jaeckle, Evanthia Galanis

Research output: Contribution to journalArticle

116 Citations (Scopus)

Abstract

Vorinostat, a histone deacetylase (HDAC) inhibitor, has shown evidence of single-agent activity in glioblastoma (GBM), and in preclinical studies, we have demonstrated significant synergistic cytotoxicity between HDAC inhibitors and proteasome inhibitors in GBM cell lines. We therefore conducted a phase II trial to evaluate the efficacy of vorinostat in combination with the proteasome inhibitor bortezomib in patients with recurrent GBM. Vorinostat was administered at a dose of 400 mg daily for 14 days of a 21-day cycle, and bortezomib was administered at a dose of 1.3 mg/m 2 intravenously on days 1, 4, 8, and 11 of the cycle. A total of 37 patients were treated, and treatment was well tolerated: grade 3, 4 nonhematologic toxicity occurred in 30% of patients and consisted mainly of fatigue (14%) and neuropathy (5%); grade 3, 4 hematologic toxicity occurred in 37 of patients and consisted of thrombocytopenia (30%), lymphopenia (4%), and neutropenia (4%). The trial was closed at the predetermined interim analysis, with 0 of 34 patients being progression-free at 6 months. One patient achieved a partial response according to the Macdonald criteria. The median time to progression for all patients was 1.5 months (range, 0.5-5.6 months), and median overall survival (OS) was 3.2 months. Patients who had received prior bevacizumab therapy had a shorter time to progression and OS, compared with those who had not. On the basis of the results of this phase II study, further evaluation of the vorinostat-bortezomib combination in GBM patients in this dose and schedule is not recommended.

Original languageEnglish (US)
Pages (from-to)215-221
Number of pages7
JournalNeuro-Oncology
Volume14
Issue number2
DOIs
StatePublished - Feb 1 2012

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Glioblastoma
Neoplasms
Proteasome Inhibitors
Histone Deacetylase Inhibitors
Therapeutics
Bortezomib
vorinostat
Lymphopenia
Survival
Neutropenia
Thrombocytopenia
Fatigue
Appointments and Schedules
Cell Line

All Science Journal Classification (ASJC) codes

  • Oncology
  • Clinical Neurology
  • Cancer Research

Cite this

Friday, B. B., Anderson, S. K., Buckner, J., Yu, C., Giannini, C., Geoffroy, F., ... Galanis, E. (2012). Phase II trial of vorinostat in combination with bortezomib in recurrent glioblastoma: A north central cancer treatment group study. Neuro-Oncology, 14(2), 215-221. https://doi.org/10.1093/neuonc/nor198
Friday, Bret B. ; Anderson, S. Keith ; Buckner, Jan ; Yu, Chunrong ; Giannini, Caterina ; Geoffroy, Francois ; Schwerkoske, John ; Mazurczak, Miroslaw ; Gross, Howard ; Pajon, Eduardo ; Jaeckle, Kurt ; Galanis, Evanthia. / Phase II trial of vorinostat in combination with bortezomib in recurrent glioblastoma : A north central cancer treatment group study. In: Neuro-Oncology. 2012 ; Vol. 14, No. 2. pp. 215-221.
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Friday, BB, Anderson, SK, Buckner, J, Yu, C, Giannini, C, Geoffroy, F, Schwerkoske, J, Mazurczak, M, Gross, H, Pajon, E, Jaeckle, K & Galanis, E 2012, 'Phase II trial of vorinostat in combination with bortezomib in recurrent glioblastoma: A north central cancer treatment group study', Neuro-Oncology, vol. 14, no. 2, pp. 215-221. https://doi.org/10.1093/neuonc/nor198

Phase II trial of vorinostat in combination with bortezomib in recurrent glioblastoma : A north central cancer treatment group study. / Friday, Bret B.; Anderson, S. Keith; Buckner, Jan; Yu, Chunrong; Giannini, Caterina; Geoffroy, Francois; Schwerkoske, John; Mazurczak, Miroslaw; Gross, Howard; Pajon, Eduardo; Jaeckle, Kurt; Galanis, Evanthia.

In: Neuro-Oncology, Vol. 14, No. 2, 01.02.2012, p. 215-221.

Research output: Contribution to journalArticle

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T1 - Phase II trial of vorinostat in combination with bortezomib in recurrent glioblastoma

T2 - A north central cancer treatment group study

AU - Friday, Bret B.

AU - Anderson, S. Keith

AU - Buckner, Jan

AU - Yu, Chunrong

AU - Giannini, Caterina

AU - Geoffroy, Francois

AU - Schwerkoske, John

AU - Mazurczak, Miroslaw

AU - Gross, Howard

AU - Pajon, Eduardo

AU - Jaeckle, Kurt

AU - Galanis, Evanthia

PY - 2012/2/1

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N2 - Vorinostat, a histone deacetylase (HDAC) inhibitor, has shown evidence of single-agent activity in glioblastoma (GBM), and in preclinical studies, we have demonstrated significant synergistic cytotoxicity between HDAC inhibitors and proteasome inhibitors in GBM cell lines. We therefore conducted a phase II trial to evaluate the efficacy of vorinostat in combination with the proteasome inhibitor bortezomib in patients with recurrent GBM. Vorinostat was administered at a dose of 400 mg daily for 14 days of a 21-day cycle, and bortezomib was administered at a dose of 1.3 mg/m 2 intravenously on days 1, 4, 8, and 11 of the cycle. A total of 37 patients were treated, and treatment was well tolerated: grade 3, 4 nonhematologic toxicity occurred in 30% of patients and consisted mainly of fatigue (14%) and neuropathy (5%); grade 3, 4 hematologic toxicity occurred in 37 of patients and consisted of thrombocytopenia (30%), lymphopenia (4%), and neutropenia (4%). The trial was closed at the predetermined interim analysis, with 0 of 34 patients being progression-free at 6 months. One patient achieved a partial response according to the Macdonald criteria. The median time to progression for all patients was 1.5 months (range, 0.5-5.6 months), and median overall survival (OS) was 3.2 months. Patients who had received prior bevacizumab therapy had a shorter time to progression and OS, compared with those who had not. On the basis of the results of this phase II study, further evaluation of the vorinostat-bortezomib combination in GBM patients in this dose and schedule is not recommended.

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