Phase II trial of Vorinostat in recurrent glioblastoma multiforme

A north central cancer treatment group study

Evanthia Galanis, Kurt A. Jaeckle, Matthew J. Maurer, Joel M. Reid, Matthew M. Ames, James S. Hardwick, John F. Reilly, Andrey Loboda, Michael Nebozhyn, Valeria R. Fantin, Victoria M. Richon, Bernd Scheithauer, Caterina Giannini, Patrick J. Flynn, Dennis F. Moore, James Zwiebel, Jan C. Buckner

Research output: Contribution to journalArticle

221 Citations (Scopus)

Abstract

Purpose Vorinostat, a histone deacetylase inhibitor, represents a rational therapeutic target in glioblastoma multiforme (GBM) Patients and Methods Patients with recurrent GBM who had received one or fewer chemotherapy regimens for progressive disease were eligible. Vorinostat was administered at a dose of 200 mg orally twice a day for 14 days, followed by a 7-day rest period Results A total of 66 patients were treated. Grade 3 or worse nonhematologic toxicity occurred in 26% of patients and consisted mainly of fatigue (17%), dehydration (6%), and hypernatremia (5%); grade 3 or worse hematologic toxicity occurred in 26% of patients and consisted mainly of thrombocytopenia (22%). Pharmacokinetic analysis showed lower vorinostat maximum concentration and area under the curve (0 to 24 hours) values in patients treated with enzyme-inducing anticonvulsants, although this did not reach statistical significance. The trial met the prospectively defined primary efficacy end point, with nine of the first 52 patients being progression-free at 6 months Median overall survival from study entry was 5.7 months (range, 0.7 to 28+ months). Immunohistochemical analysis performed in paired baseline and post-vorinostat treatment samples in a separate surgical subgroup of five patients with recurrent GBM showed post treatment increase in acetylation of histones H2B and H4 (four of five patients) and of histone H3 (three of five patients). Microarray RNA analysis in the same samples showed changes in genes regulated by vorinostat, such as upregulation of E-cadherin (P = .02). Conclusion Vorinostat monotherapy is well tolerated in patients with recurrent GBM and has modest single-agent activity. Histone acetylation analysis and RNA expression profiling indicate that vorinostat in this dose and schedule affects target pathways in GBM. Additional testing of vorinostat in combination regimens is warranted

Original languageEnglish (US)
Pages (from-to)2052-2058
Number of pages7
JournalJournal of Clinical Oncology
Volume27
Issue number12
DOIs
StatePublished - Apr 20 2009

Fingerprint

Glioblastoma
Neoplasms
Therapeutics
Histones
Acetylation
vorinostat
RNA
Hypernatremia
Histone Deacetylase Inhibitors
Cadherins
Microarray Analysis
Dehydration
Thrombocytopenia
Anticonvulsants
Area Under Curve
Fatigue
Appointments and Schedules
Up-Regulation
Pharmacokinetics
Drug Therapy

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Galanis, E., Jaeckle, K. A., Maurer, M. J., Reid, J. M., Ames, M. M., Hardwick, J. S., ... Buckner, J. C. (2009). Phase II trial of Vorinostat in recurrent glioblastoma multiforme: A north central cancer treatment group study. Journal of Clinical Oncology, 27(12), 2052-2058. https://doi.org/10.1200/JCO.2008.19.0694
Galanis, Evanthia ; Jaeckle, Kurt A. ; Maurer, Matthew J. ; Reid, Joel M. ; Ames, Matthew M. ; Hardwick, James S. ; Reilly, John F. ; Loboda, Andrey ; Nebozhyn, Michael ; Fantin, Valeria R. ; Richon, Victoria M. ; Scheithauer, Bernd ; Giannini, Caterina ; Flynn, Patrick J. ; Moore, Dennis F. ; Zwiebel, James ; Buckner, Jan C. / Phase II trial of Vorinostat in recurrent glioblastoma multiforme : A north central cancer treatment group study. In: Journal of Clinical Oncology. 2009 ; Vol. 27, No. 12. pp. 2052-2058.
@article{8cd419b826b94e29872b25897b48d168,
title = "Phase II trial of Vorinostat in recurrent glioblastoma multiforme: A north central cancer treatment group study",
abstract = "Purpose Vorinostat, a histone deacetylase inhibitor, represents a rational therapeutic target in glioblastoma multiforme (GBM) Patients and Methods Patients with recurrent GBM who had received one or fewer chemotherapy regimens for progressive disease were eligible. Vorinostat was administered at a dose of 200 mg orally twice a day for 14 days, followed by a 7-day rest period Results A total of 66 patients were treated. Grade 3 or worse nonhematologic toxicity occurred in 26{\%} of patients and consisted mainly of fatigue (17{\%}), dehydration (6{\%}), and hypernatremia (5{\%}); grade 3 or worse hematologic toxicity occurred in 26{\%} of patients and consisted mainly of thrombocytopenia (22{\%}). Pharmacokinetic analysis showed lower vorinostat maximum concentration and area under the curve (0 to 24 hours) values in patients treated with enzyme-inducing anticonvulsants, although this did not reach statistical significance. The trial met the prospectively defined primary efficacy end point, with nine of the first 52 patients being progression-free at 6 months Median overall survival from study entry was 5.7 months (range, 0.7 to 28+ months). Immunohistochemical analysis performed in paired baseline and post-vorinostat treatment samples in a separate surgical subgroup of five patients with recurrent GBM showed post treatment increase in acetylation of histones H2B and H4 (four of five patients) and of histone H3 (three of five patients). Microarray RNA analysis in the same samples showed changes in genes regulated by vorinostat, such as upregulation of E-cadherin (P = .02). Conclusion Vorinostat monotherapy is well tolerated in patients with recurrent GBM and has modest single-agent activity. Histone acetylation analysis and RNA expression profiling indicate that vorinostat in this dose and schedule affects target pathways in GBM. Additional testing of vorinostat in combination regimens is warranted",
author = "Evanthia Galanis and Jaeckle, {Kurt A.} and Maurer, {Matthew J.} and Reid, {Joel M.} and Ames, {Matthew M.} and Hardwick, {James S.} and Reilly, {John F.} and Andrey Loboda and Michael Nebozhyn and Fantin, {Valeria R.} and Richon, {Victoria M.} and Bernd Scheithauer and Caterina Giannini and Flynn, {Patrick J.} and Moore, {Dennis F.} and James Zwiebel and Buckner, {Jan C.}",
year = "2009",
month = "4",
day = "20",
doi = "10.1200/JCO.2008.19.0694",
language = "English (US)",
volume = "27",
pages = "2052--2058",
journal = "Journal of Clinical Oncology",
issn = "0732-183X",
publisher = "American Society of Clinical Oncology",
number = "12",

}

Galanis, E, Jaeckle, KA, Maurer, MJ, Reid, JM, Ames, MM, Hardwick, JS, Reilly, JF, Loboda, A, Nebozhyn, M, Fantin, VR, Richon, VM, Scheithauer, B, Giannini, C, Flynn, PJ, Moore, DF, Zwiebel, J & Buckner, JC 2009, 'Phase II trial of Vorinostat in recurrent glioblastoma multiforme: A north central cancer treatment group study', Journal of Clinical Oncology, vol. 27, no. 12, pp. 2052-2058. https://doi.org/10.1200/JCO.2008.19.0694

Phase II trial of Vorinostat in recurrent glioblastoma multiforme : A north central cancer treatment group study. / Galanis, Evanthia; Jaeckle, Kurt A.; Maurer, Matthew J.; Reid, Joel M.; Ames, Matthew M.; Hardwick, James S.; Reilly, John F.; Loboda, Andrey; Nebozhyn, Michael; Fantin, Valeria R.; Richon, Victoria M.; Scheithauer, Bernd; Giannini, Caterina; Flynn, Patrick J.; Moore, Dennis F.; Zwiebel, James; Buckner, Jan C.

In: Journal of Clinical Oncology, Vol. 27, No. 12, 20.04.2009, p. 2052-2058.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Phase II trial of Vorinostat in recurrent glioblastoma multiforme

T2 - A north central cancer treatment group study

AU - Galanis, Evanthia

AU - Jaeckle, Kurt A.

AU - Maurer, Matthew J.

AU - Reid, Joel M.

AU - Ames, Matthew M.

AU - Hardwick, James S.

AU - Reilly, John F.

AU - Loboda, Andrey

AU - Nebozhyn, Michael

AU - Fantin, Valeria R.

AU - Richon, Victoria M.

AU - Scheithauer, Bernd

AU - Giannini, Caterina

AU - Flynn, Patrick J.

AU - Moore, Dennis F.

AU - Zwiebel, James

AU - Buckner, Jan C.

PY - 2009/4/20

Y1 - 2009/4/20

N2 - Purpose Vorinostat, a histone deacetylase inhibitor, represents a rational therapeutic target in glioblastoma multiforme (GBM) Patients and Methods Patients with recurrent GBM who had received one or fewer chemotherapy regimens for progressive disease were eligible. Vorinostat was administered at a dose of 200 mg orally twice a day for 14 days, followed by a 7-day rest period Results A total of 66 patients were treated. Grade 3 or worse nonhematologic toxicity occurred in 26% of patients and consisted mainly of fatigue (17%), dehydration (6%), and hypernatremia (5%); grade 3 or worse hematologic toxicity occurred in 26% of patients and consisted mainly of thrombocytopenia (22%). Pharmacokinetic analysis showed lower vorinostat maximum concentration and area under the curve (0 to 24 hours) values in patients treated with enzyme-inducing anticonvulsants, although this did not reach statistical significance. The trial met the prospectively defined primary efficacy end point, with nine of the first 52 patients being progression-free at 6 months Median overall survival from study entry was 5.7 months (range, 0.7 to 28+ months). Immunohistochemical analysis performed in paired baseline and post-vorinostat treatment samples in a separate surgical subgroup of five patients with recurrent GBM showed post treatment increase in acetylation of histones H2B and H4 (four of five patients) and of histone H3 (three of five patients). Microarray RNA analysis in the same samples showed changes in genes regulated by vorinostat, such as upregulation of E-cadherin (P = .02). Conclusion Vorinostat monotherapy is well tolerated in patients with recurrent GBM and has modest single-agent activity. Histone acetylation analysis and RNA expression profiling indicate that vorinostat in this dose and schedule affects target pathways in GBM. Additional testing of vorinostat in combination regimens is warranted

AB - Purpose Vorinostat, a histone deacetylase inhibitor, represents a rational therapeutic target in glioblastoma multiforme (GBM) Patients and Methods Patients with recurrent GBM who had received one or fewer chemotherapy regimens for progressive disease were eligible. Vorinostat was administered at a dose of 200 mg orally twice a day for 14 days, followed by a 7-day rest period Results A total of 66 patients were treated. Grade 3 or worse nonhematologic toxicity occurred in 26% of patients and consisted mainly of fatigue (17%), dehydration (6%), and hypernatremia (5%); grade 3 or worse hematologic toxicity occurred in 26% of patients and consisted mainly of thrombocytopenia (22%). Pharmacokinetic analysis showed lower vorinostat maximum concentration and area under the curve (0 to 24 hours) values in patients treated with enzyme-inducing anticonvulsants, although this did not reach statistical significance. The trial met the prospectively defined primary efficacy end point, with nine of the first 52 patients being progression-free at 6 months Median overall survival from study entry was 5.7 months (range, 0.7 to 28+ months). Immunohistochemical analysis performed in paired baseline and post-vorinostat treatment samples in a separate surgical subgroup of five patients with recurrent GBM showed post treatment increase in acetylation of histones H2B and H4 (four of five patients) and of histone H3 (three of five patients). Microarray RNA analysis in the same samples showed changes in genes regulated by vorinostat, such as upregulation of E-cadherin (P = .02). Conclusion Vorinostat monotherapy is well tolerated in patients with recurrent GBM and has modest single-agent activity. Histone acetylation analysis and RNA expression profiling indicate that vorinostat in this dose and schedule affects target pathways in GBM. Additional testing of vorinostat in combination regimens is warranted

UR - http://www.scopus.com/inward/record.url?scp=65349141942&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=65349141942&partnerID=8YFLogxK

U2 - 10.1200/JCO.2008.19.0694

DO - 10.1200/JCO.2008.19.0694

M3 - Article

VL - 27

SP - 2052

EP - 2058

JO - Journal of Clinical Oncology

JF - Journal of Clinical Oncology

SN - 0732-183X

IS - 12

ER -