title: A phase I trial of vorinostat and bortezomib in children with refractory or recurrent solid tumors: a Children's Oncology Group phase I consortium study (ADVL0916).
abstract: BACKGROUND
  A pediatric Phase I trial was performed to determine the maximum-tolerated dose, dose-limiting toxicities (DLTs), and pharmacokinetics (PK) of vorinostat and bortezomib, in patients with solid tumors.
  
  
  METHODS
  Oral vorinostat was administered on days 1-5 and 8-12 of a 21-day cycle (starting dose 180 mg/m(2) /day with dose escalations to 230 and 300 mg/m(2) /day). Bortezomib (1.3 mg/m(2) i.v.) was administered on days 1, 4, 8, and 11 of the same cycle. PK and correlative biology studies were performed during Cycle 1.
  
  
  RESULTS
  Twenty-three eligible patients [17 male, median age 12 years (range: 1-20)] were enrolled of whom 17 were fully evaluable for toxicity. Cycle 1 DLTs that occurred in 2/6 patients at dose level 3 (vorinostat 300 mg/m(2) /day) were Grade 2 sensory neuropathy that progressed to Grade 4 (n = 1) and Grade 3 nausea and anorexia (n = 1). No objective responses were observed. There was wide interpatient variability in vorinostat PK parameters. Bortezomib disposition was best described by a three-compartment model that demonstrated rapid distribution followed by prolonged elimination. We did not observe a decrease in nuclear factor-κB activity or Grp78 induction after bortezomib treatment in peripheral blood mononuclear cells from solid tumor patients.
  
  
  CONCLUSIONS
  The recommended Phase 2 dose and schedule is vorinostat (230 mg/m(2) /day PO on days 1-5 and 8-12) in combination with bortezomib (1.3 mg/m(2) /day i.v. on days 1, 4, 8, and 11 of a 21-day cycle) in children with recurrent or refractory solid tumors.
authors.affiliation: Texas Children's Cancer Center and Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030, USA. jamuscal@txch.org
authors.forename: Jodi A
authors.initials: JA
authors.lastname: Muscal
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Thompson
authors.forename: Terzah M
authors.initials: TM
authors.lastname: Horton
authors.forename: Ashish M
authors.initials: AM
authors.lastname: Ingle
authors.forename: Charlotte H
authors.initials: CH
authors.lastname: Ahern
authors.forename: Renee M
authors.initials: RM
authors.lastname: McGovern
authors.forename: Joel M
authors.initials: JM
authors.lastname: Reid
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Ames
authors.forename: Igor
authors.initials: I
authors.lastname: Espinoza-Delgado
authors.forename: Brenda J
authors.initials: BJ
authors.lastname: Weigel
authors.forename: Susan M
authors.initials: SM
authors.lastname: Blaney
mesh_terms: D000293:Adolescent; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001897:Boronic Acids / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D000069286:Bortezomib; D002648:Child; D002675:Child, Preschool; D004305:Dose-Response Relationship, Drug; D000091342:Endoplasmic Reticulum Chaperone BiP; D005260:Female; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D007223:Infant; D008297:Male; D020714:Maximum Tolerated Dose; D009369:Neoplasms / Q000188:drug therapy*; D011719:Pyrazines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D000077337:Vorinostat; D055815:Young Adult
chemical_list: D001897:Boronic Acids; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D006877:Hydroxamic Acids; D011719:Pyrazines; D000077337:Vorinostat; D000069286:Bortezomib