title: Phase II trial of vorinostat in combination with bortezomib in recurrent glioblastoma: a north central cancer treatment group study.
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.
authors.affiliation: Essentia Health-Duluth Clinic Cancer Center, Duluth, Minnesota, USA.
authors.forename: Bret B
authors.initials: BB
authors.lastname: Friday
authors.forename: S Keith
authors.initials: SK
authors.lastname: Anderson
authors.forename: Jan
authors.initials: J
authors.lastname: Buckner
authors.forename: Chunrong
authors.initials: C
authors.lastname: Yu
authors.forename: Caterina
authors.initials: C
authors.lastname: Giannini
authors.forename: Francois
authors.initials: F
authors.lastname: Geoffroy
authors.forename: John
authors.initials: J
authors.lastname: Schwerkoske
authors.forename: Miroslaw
authors.initials: M
authors.lastname: Mazurczak
authors.forename: Howard
authors.initials: H
authors.lastname: Gross
authors.forename: Eduardo
authors.initials: E
authors.lastname: Pajon
authors.forename: Kurt
authors.initials: K
authors.lastname: Jaeckle
authors.forename: Evanthia
authors.initials: E
authors.lastname: Galanis
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001897:Boronic Acids / Q000008:administration & dosage / Q000627:therapeutic use*; D000069286:Bortezomib; D001932:Brain Neoplasms / Q000188:drug therapy*; D018450:Disease Progression; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy* / Q000401:mortality; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D011719:Pyrazines / Q000008:administration & dosage / Q000627:therapeutic use*; D016019:Survival Analysis; D000077337:Vorinostat
chemical_list: D001897:Boronic Acids; D006877:Hydroxamic Acids; D011719:Pyrazines; D000077337:Vorinostat; D000069286:Bortezomib
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