Phase I/II trial of vorinostat combined with temozolomide and radiation therapy for newly diagnosed glioblastoma

Results of Alliance N0874/ABTC 02

Evanthia Galanis, S. Keith Anderson, C. Ryan Miller, Jann N. Sarkaria, Kurt Jaeckle, Jan C. Buckner, Keith L. Ligon, Karla V. Ballman, Dennis F. Moore, Michael Nebozhyn, Andrey Loboda, David Schiff, Manmeet Singh Ahluwalia, Eudocia Q. Lee, Elizabeth R. Gerstner, Glenn J. Lesser, Michael Prados, Stuart A. Grossman, Jane Cerhan, Caterina Giannini & 1 others Patrick Y. Wen

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

Background Vorinostat, a histone deacetylase (HDAC) inhibitor, has shown radiosensitizing properties in preclinical studies. This open-label, single-arm trial evaluated the maximum tolerated dose (MTD; phase I) and efficacy (phase II) of vorinostat combined with standard chemoradiation in newly diagnosed glioblastoma. Methods Patients received oral vorinostat (300 or 400 mg/day) on days 1-5 weekly during temozolomide chemoradiation. Following a 4-to 6-week rest, patients received up to 12 cycles of standard adjuvant temozolomide and vorinostat (400 mg/day) on days 1-7 and 15-21 of each 28-day cycle. Association between vorinostat response signatures and progression-free survival (PFS) and overall survival (OS) was assessed based on RNA sequencing of baseline tumor tissue. Results Phase I and phase II enrolled 15 and 107 patients, respectively. The combination therapy MTD was vorinostat 300 mg/day and temozolomide 75 mg/m 2/day. Dose-limiting toxicities were grade 4 neutropenia and thrombocytopenia and grade 3 aspartate aminotransferase elevation, hyperglycemia, fatigue, and wound dehiscence. The primary efficacy endpoint in the phase II cohort, OS rate at 15 months, was 55.1% (median OS 16.1 mo), and consequently, the study did not meet its efficacy objective. Most common treatment-related grade 3/4 toxicities in the phase II component were lymphopenia (32.7%), thrombocytopenia (28.0%), and neutropenia (21.5%). RNA expression profiling of baseline tumors (N = 76) demonstrated that vorinostat resistance (sig-79) and sensitivity (sig-139) signatures had a reverse and positive association with OS/PFS, respectively. Conclusions Vorinostat combined with standard chemoradiation had acceptable tolerability in newly diagnosed glioblastoma. Although the primary efficacy endpoint was not met, vorinostat sensitivity and resistance signatures could facilitate patient selection in future trials.

Original languageEnglish (US)
Pages (from-to)546-556
Number of pages11
JournalNeuro-Oncology
Volume20
Issue number4
DOIs
StatePublished - Mar 27 2018

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temozolomide
Glioblastoma
Radiotherapy
Neutropenia
Disease-Free Survival
Survival
RNA Sequence Analysis
vorinostat
Lymphopenia
Histone Deacetylase Inhibitors
Maximum Tolerated Dose
Aspartate Aminotransferases

All Science Journal Classification (ASJC) codes

  • Oncology
  • Clinical Neurology
  • Cancer Research

Cite this

Galanis, E., Keith Anderson, S., Miller, C. R., Sarkaria, J. N., Jaeckle, K., Buckner, J. C., ... Wen, P. Y. (2018). Phase I/II trial of vorinostat combined with temozolomide and radiation therapy for newly diagnosed glioblastoma: Results of Alliance N0874/ABTC 02. Neuro-Oncology, 20(4), 546-556. https://doi.org/10.1093/neuonc/nox161
Galanis, Evanthia ; Keith Anderson, S. ; Miller, C. Ryan ; Sarkaria, Jann N. ; Jaeckle, Kurt ; Buckner, Jan C. ; Ligon, Keith L. ; Ballman, Karla V. ; Moore, Dennis F. ; Nebozhyn, Michael ; Loboda, Andrey ; Schiff, David ; Ahluwalia, Manmeet Singh ; Lee, Eudocia Q. ; Gerstner, Elizabeth R. ; Lesser, Glenn J. ; Prados, Michael ; Grossman, Stuart A. ; Cerhan, Jane ; Giannini, Caterina ; Wen, Patrick Y. / Phase I/II trial of vorinostat combined with temozolomide and radiation therapy for newly diagnosed glioblastoma : Results of Alliance N0874/ABTC 02. In: Neuro-Oncology. 2018 ; Vol. 20, No. 4. pp. 546-556.
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abstract = "Background Vorinostat, a histone deacetylase (HDAC) inhibitor, has shown radiosensitizing properties in preclinical studies. This open-label, single-arm trial evaluated the maximum tolerated dose (MTD; phase I) and efficacy (phase II) of vorinostat combined with standard chemoradiation in newly diagnosed glioblastoma. Methods Patients received oral vorinostat (300 or 400 mg/day) on days 1-5 weekly during temozolomide chemoradiation. Following a 4-to 6-week rest, patients received up to 12 cycles of standard adjuvant temozolomide and vorinostat (400 mg/day) on days 1-7 and 15-21 of each 28-day cycle. Association between vorinostat response signatures and progression-free survival (PFS) and overall survival (OS) was assessed based on RNA sequencing of baseline tumor tissue. Results Phase I and phase II enrolled 15 and 107 patients, respectively. The combination therapy MTD was vorinostat 300 mg/day and temozolomide 75 mg/m 2/day. Dose-limiting toxicities were grade 4 neutropenia and thrombocytopenia and grade 3 aspartate aminotransferase elevation, hyperglycemia, fatigue, and wound dehiscence. The primary efficacy endpoint in the phase II cohort, OS rate at 15 months, was 55.1{\%} (median OS 16.1 mo), and consequently, the study did not meet its efficacy objective. Most common treatment-related grade 3/4 toxicities in the phase II component were lymphopenia (32.7{\%}), thrombocytopenia (28.0{\%}), and neutropenia (21.5{\%}). RNA expression profiling of baseline tumors (N = 76) demonstrated that vorinostat resistance (sig-79) and sensitivity (sig-139) signatures had a reverse and positive association with OS/PFS, respectively. Conclusions Vorinostat combined with standard chemoradiation had acceptable tolerability in newly diagnosed glioblastoma. Although the primary efficacy endpoint was not met, vorinostat sensitivity and resistance signatures could facilitate patient selection in future trials.",
author = "Evanthia Galanis and {Keith Anderson}, S. and Miller, {C. Ryan} and Sarkaria, {Jann N.} and Kurt Jaeckle and Buckner, {Jan C.} and Ligon, {Keith L.} and Ballman, {Karla V.} and Moore, {Dennis F.} and Michael Nebozhyn and Andrey Loboda and David Schiff and Ahluwalia, {Manmeet Singh} and Lee, {Eudocia Q.} and Gerstner, {Elizabeth R.} and Lesser, {Glenn J.} and Michael Prados and Grossman, {Stuart A.} and Jane Cerhan and Caterina Giannini and Wen, {Patrick Y.}",
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Galanis, E, Keith Anderson, S, Miller, CR, Sarkaria, JN, Jaeckle, K, Buckner, JC, Ligon, KL, Ballman, KV, Moore, DF, Nebozhyn, M, Loboda, A, Schiff, D, Ahluwalia, MS, Lee, EQ, Gerstner, ER, Lesser, GJ, Prados, M, Grossman, SA, Cerhan, J, Giannini, C & Wen, PY 2018, 'Phase I/II trial of vorinostat combined with temozolomide and radiation therapy for newly diagnosed glioblastoma: Results of Alliance N0874/ABTC 02', Neuro-Oncology, vol. 20, no. 4, pp. 546-556. https://doi.org/10.1093/neuonc/nox161

Phase I/II trial of vorinostat combined with temozolomide and radiation therapy for newly diagnosed glioblastoma : Results of Alliance N0874/ABTC 02. / Galanis, Evanthia; Keith Anderson, S.; Miller, C. Ryan; Sarkaria, Jann N.; Jaeckle, Kurt; Buckner, Jan C.; Ligon, Keith L.; Ballman, Karla V.; Moore, Dennis F.; Nebozhyn, Michael; Loboda, Andrey; Schiff, David; Ahluwalia, Manmeet Singh; Lee, Eudocia Q.; Gerstner, Elizabeth R.; Lesser, Glenn J.; Prados, Michael; Grossman, Stuart A.; Cerhan, Jane; Giannini, Caterina; Wen, Patrick Y.

In: Neuro-Oncology, Vol. 20, No. 4, 27.03.2018, p. 546-556.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Phase I/II trial of vorinostat combined with temozolomide and radiation therapy for newly diagnosed glioblastoma

T2 - Results of Alliance N0874/ABTC 02

AU - Galanis, Evanthia

AU - Keith Anderson, S.

AU - Miller, C. Ryan

AU - Sarkaria, Jann N.

AU - Jaeckle, Kurt

AU - Buckner, Jan C.

AU - Ligon, Keith L.

AU - Ballman, Karla V.

AU - Moore, Dennis F.

AU - Nebozhyn, Michael

AU - Loboda, Andrey

AU - Schiff, David

AU - Ahluwalia, Manmeet Singh

AU - Lee, Eudocia Q.

AU - Gerstner, Elizabeth R.

AU - Lesser, Glenn J.

AU - Prados, Michael

AU - Grossman, Stuart A.

AU - Cerhan, Jane

AU - Giannini, Caterina

AU - Wen, Patrick Y.

PY - 2018/3/27

Y1 - 2018/3/27

N2 - Background Vorinostat, a histone deacetylase (HDAC) inhibitor, has shown radiosensitizing properties in preclinical studies. This open-label, single-arm trial evaluated the maximum tolerated dose (MTD; phase I) and efficacy (phase II) of vorinostat combined with standard chemoradiation in newly diagnosed glioblastoma. Methods Patients received oral vorinostat (300 or 400 mg/day) on days 1-5 weekly during temozolomide chemoradiation. Following a 4-to 6-week rest, patients received up to 12 cycles of standard adjuvant temozolomide and vorinostat (400 mg/day) on days 1-7 and 15-21 of each 28-day cycle. Association between vorinostat response signatures and progression-free survival (PFS) and overall survival (OS) was assessed based on RNA sequencing of baseline tumor tissue. Results Phase I and phase II enrolled 15 and 107 patients, respectively. The combination therapy MTD was vorinostat 300 mg/day and temozolomide 75 mg/m 2/day. Dose-limiting toxicities were grade 4 neutropenia and thrombocytopenia and grade 3 aspartate aminotransferase elevation, hyperglycemia, fatigue, and wound dehiscence. The primary efficacy endpoint in the phase II cohort, OS rate at 15 months, was 55.1% (median OS 16.1 mo), and consequently, the study did not meet its efficacy objective. Most common treatment-related grade 3/4 toxicities in the phase II component were lymphopenia (32.7%), thrombocytopenia (28.0%), and neutropenia (21.5%). RNA expression profiling of baseline tumors (N = 76) demonstrated that vorinostat resistance (sig-79) and sensitivity (sig-139) signatures had a reverse and positive association with OS/PFS, respectively. Conclusions Vorinostat combined with standard chemoradiation had acceptable tolerability in newly diagnosed glioblastoma. Although the primary efficacy endpoint was not met, vorinostat sensitivity and resistance signatures could facilitate patient selection in future trials.

AB - Background Vorinostat, a histone deacetylase (HDAC) inhibitor, has shown radiosensitizing properties in preclinical studies. This open-label, single-arm trial evaluated the maximum tolerated dose (MTD; phase I) and efficacy (phase II) of vorinostat combined with standard chemoradiation in newly diagnosed glioblastoma. Methods Patients received oral vorinostat (300 or 400 mg/day) on days 1-5 weekly during temozolomide chemoradiation. Following a 4-to 6-week rest, patients received up to 12 cycles of standard adjuvant temozolomide and vorinostat (400 mg/day) on days 1-7 and 15-21 of each 28-day cycle. Association between vorinostat response signatures and progression-free survival (PFS) and overall survival (OS) was assessed based on RNA sequencing of baseline tumor tissue. Results Phase I and phase II enrolled 15 and 107 patients, respectively. The combination therapy MTD was vorinostat 300 mg/day and temozolomide 75 mg/m 2/day. Dose-limiting toxicities were grade 4 neutropenia and thrombocytopenia and grade 3 aspartate aminotransferase elevation, hyperglycemia, fatigue, and wound dehiscence. The primary efficacy endpoint in the phase II cohort, OS rate at 15 months, was 55.1% (median OS 16.1 mo), and consequently, the study did not meet its efficacy objective. Most common treatment-related grade 3/4 toxicities in the phase II component were lymphopenia (32.7%), thrombocytopenia (28.0%), and neutropenia (21.5%). RNA expression profiling of baseline tumors (N = 76) demonstrated that vorinostat resistance (sig-79) and sensitivity (sig-139) signatures had a reverse and positive association with OS/PFS, respectively. Conclusions Vorinostat combined with standard chemoradiation had acceptable tolerability in newly diagnosed glioblastoma. Although the primary efficacy endpoint was not met, vorinostat sensitivity and resistance signatures could facilitate patient selection in future trials.

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DO - 10.1093/neuonc/nox161

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JF - Neuro-Oncology

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