title: A pediatric phase 1 trial of vorinostat and temozolomide in relapsed or refractory primary brain or spinal cord tumors: a Children's Oncology Group phase 1 consortium study.
abstract: OBJECTIVE
  We conducted a pediatric phase I study to estimate the maximum tolerated dose (MTD), dose-limiting toxicities (DLT), and pharmacokinetic properties of vorinostat, a histone deacetylase (HDAC) inhibitor, when given in combination with temozolomide in children with refractory or recurrent CNS malignancies.
  
  
  METHODS
  Vorinostat, followed by temozolomide approximately 1 hour later, was orally administered, once daily, for 5 consecutive days every 28 days at three dose levels using the rolling six design. Studies of histone accumulation in peripheral blood mononuclear cells were performed on Day 1 at 0, 6, and 24 hours after vorinostat dosing. Vorinostat pharmacokinetics (PK) and serum MGMT promoter status were also assessed.
  
  
  RESULTS
  Nineteen eligible patients were enrolled and 18 patients were evaluable for toxicity. There were no DLTs observed at dose level 1 or 2. DLTs occurred in four patients at dose level 3: thrombocytopenia (4), neutropenia (3), and leucopenia (1). Non-dose limiting grade 3 or 4 toxicities related to protocol therapy were also hematologic and included neutropenia, lymphopenia, thrombocytopenia, anemia, and leucopenia. Three patients exhibited stable disease and one patient had a partial response. There was no clear relationship between vorinostat dosage and drug exposure over the dose range studied. Accumulation of acetylated H3 histone in PBMC was observed after administration of vorinostat.
  
  
  CONCLUSIONS
  Five-day cycles of vorinostat in combination with temozolomide are well tolerated in children with recurrent CNS malignancies with myelosuppression as the DLT. The recommended phase II combination doses are vorinostat, 300 mg/m(2) /day and temozolomide, 150 mg/m(2) /day.
authors.affiliation: Division of Oncology, Cincinnati Children's Hospital Medical Center, Cancer and Blood Diseases Institute, Cincinnati, Ohio 45229, USA. trent.hummel@cchmc.org
authors.forename: Trent R
authors.initials: TR
authors.lastname: Hummel
authors.forename: Lars
authors.initials: L
authors.lastname: Wagner
authors.forename: Charlotte
authors.initials: C
authors.lastname: Ahern
authors.forename: Maryam
authors.initials: M
authors.lastname: Fouladi
authors.forename: Joel M
authors.initials: JM
authors.lastname: Reid
authors.forename: Renee M
authors.initials: RM
authors.lastname: McGovern
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Ames
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Gilbertson
authors.forename: Terzah
authors.initials: T
authors.lastname: Horton
authors.forename: Ashish M
authors.initials: AM
authors.lastname: Ingle
authors.forename: Brenda
authors.initials: B
authors.lastname: Weigel
authors.forename: Susan M
authors.initials: SM
authors.lastname: Blaney
mesh_terms: D000293:Adolescent; D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects; D001932:Brain Neoplasms / Q000097:blood / Q000188:drug therapy*; D002648:Child; D002675:Child, Preschool; D015254:DNA Modification Methylases / Q000378:metabolism; D045643:DNA Repair Enzymes / Q000378:metabolism; D003606:Dacarbazine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D004305:Dose-Response Relationship, Drug; D005260:Female; D006657:Histones / Q000097:blood; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage / Q000009:adverse effects; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008297:Male; D020714:Maximum Tolerated Dose; D009503:Neutropenia / Q000097:blood / Q000139:chemically induced; D011401:Promoter Regions, Genetic; D012008:Recurrence; D013120:Spinal Cord Neoplasms / Q000097:blood / Q000188:drug therapy*; D000077204:Temozolomide; D013921:Thrombocytopenia / Q000097:blood / Q000139:chemically induced; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D000077337:Vorinostat
chemical_list: D006657:Histones; D006877:Hydroxamic Acids; D025521:Tumor Suppressor Proteins; D000077337:Vorinostat; D003606:Dacarbazine; D015254:DNA Modification Methylases; C515491:MGMT protein, human; D045643:DNA Repair Enzymes; D000077204:Temozolomide
keywords: Children's Oncology Group; pediatric cancer; temozolomide phase I trial; vorinostat
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