Phase I/II trial of vorinostat combined with temozolomide and radiation therapy for newly diagnosed glioblastoma: results of Alliance N0874/ABTC 02.

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/m2/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.

• Authors: 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 Jr, 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, Patrick Y Wen, Alliance for Clinical Trials in Oncology and ABTC
• Journal: Neuro-oncology (Neuro Oncol) Vol. 20 Issue 4 Pg. 546-556 (03 27 2018) ISSN: 1523-5866 [Electronic] England
• PMID: 29016887 (Publication Type: Clinical Trial, Phase I, Clinical Trial, Phase II, Journal Article, Multicenter Study, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Vorinostat
• Temozolomide

Topics

• Adult
• Aged
• Aged, 80 and over
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Brain Neoplasms (pathology, therapy)
• Chemoradiotherapy
• Cohort Studies
• Female
• Follow-Up Studies
• Glioblastoma (pathology, therapy)
• Humans
• Male
• Maximum Tolerated Dose
• Middle Aged
• Prognosis
• Survival Rate
• Temozolomide (administration & dosage)
• Vorinostat (administration & dosage)
• Young Adult