title: Phase I study of vorinostat in combination with temozolomide in patients with high-grade gliomas: North American Brain Tumor Consortium Study 04-03.
abstract: OBJECTIVE
  A phase I, dose-finding study of vorinostat in combination with temozolomide (TMZ) was conducted to determine the maximum tolerated dose (MTD), safety, and pharmacokinetics in patients with high-grade glioma (HGG).
  
  
  METHODS
  This phase I, dose-finding, investigational study was conducted in two parts. Part 1 was a dose-escalation study of vorinostat in combination with TMZ 150 mg/m(2)/day for 5 days every 28 days. Part 2 was a dose-escalation study of vorinostat in combination with TMZ 150 mg/m(2)/day for 5 days of the first cycle and 200 mg/m(2)/day for 5 days of the subsequent 28-day cycles.
  
  
  RESULTS
  In part 1, the MTD of vorinostat administered on days 1 to 7 and 15 to 21 of every 28-day cycle, in combination with TMZ, was 500 mg daily. Dose-limiting toxicities (DLT) included grade 3 anorexia, grade 3 ALT, and grade 5 hemorrhage in the setting of grade 4 thrombocytopenia. In part 2, the MTD of vorinostat on days 1 to 7 and 15 to 21 of every 28-day cycle, combined with TMZ, was 400 mg daily. No DLTs were encountered, but vorinostat dosing could not be escalated further due to thrombocytopenia. The most common serious adverse events were fatigue, lymphopenia, thrombocytopenia, and thromboembolic events. There were no apparent pharmacokinetic interactions between vorinostat and TMZ. Vorinostat treatment resulted in hyperacetylation of histones H3 and H4 in peripheral mononuclear cells.
  
  
  CONCLUSIONS
  Vorinostat in combination with temozolomide is well tolerated in patients with HGG. A phase I/II trial of vorinostat with radiotherapy and concomitant TMZ in newly diagnosed glioblastoma is underway.
authors.affiliation: Center for Neuro-Oncology, Dana Farber/Brigham and Women's Cancer Center, Boston, Massachusetts 02215, USA.
authors.forename: Eudocia Q
authors.initials: EQ
authors.lastname: Lee
authors.forename: Vinay K
authors.initials: VK
authors.lastname: Puduvalli
authors.forename: Joel M
authors.initials: JM
authors.lastname: Reid
authors.forename: John G
authors.initials: JG
authors.lastname: Kuhn
authors.forename: Kathleen R
authors.initials: KR
authors.lastname: Lamborn
authors.forename: Timothy F
authors.initials: TF
authors.lastname: Cloughesy
authors.forename: Susan M
authors.initials: SM
authors.lastname: Chang
authors.forename: Jan
authors.initials: J
authors.lastname: Drappatz
authors.forename: W K Alfred
authors.initials: WK
authors.lastname: Yung
authors.forename: Mark R
authors.initials: MR
authors.lastname: Gilbert
authors.forename: H Ian
authors.initials: HI
authors.lastname: Robins
authors.forename: Frank S
authors.initials: FS
authors.lastname: Lieberman
authors.forename: Andrew B
authors.initials: AB
authors.lastname: Lassman
authors.forename: Renee M
authors.initials: RM
authors.lastname: McGovern
authors.forename: Jihong
authors.initials: J
authors.lastname: Xu
authors.forename: Serena
authors.initials: S
authors.lastname: Desideri
authors.forename: Xiabu
authors.initials: X
authors.lastname: Ye
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Ames
authors.forename: Igor
authors.initials: I
authors.lastname: Espinoza-Delgado
authors.forename: Michael D
authors.initials: MD
authors.lastname: Prados
authors.forename: Patrick Y
authors.initials: PY
authors.lastname: Wen
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives; D005260:Female; D005910:Glioma / Q000188:drug therapy* / Q000473:pathology*; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D000077204:Temozolomide; D016896:Treatment Outcome; D000077337:Vorinostat
chemical_list: D006877:Hydroxamic Acids; D000077337:Vorinostat; D003606:Dacarbazine; D000077204:Temozolomide