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)

Pediatr Blood Cancer. 2013 Mar;60(3):390-5. doi: 10.1002/pbc.24271. Epub 2012 Aug 9.

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.

Procedure: 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.

Conclusion: 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.

Publication types

  • Clinical Trial, Phase I
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Antineoplastic Combined Chemotherapy Protocols / pharmacokinetics
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Boronic Acids / administration & dosage
  • Boronic Acids / adverse effects
  • Boronic Acids / pharmacokinetics
  • Bortezomib
  • Child
  • Child, Preschool
  • Dose-Response Relationship, Drug
  • Female
  • Humans
  • Hydroxamic Acids / administration & dosage
  • Hydroxamic Acids / adverse effects
  • Hydroxamic Acids / pharmacokinetics
  • Infant
  • Male
  • Maximum Tolerated Dose
  • Neoplasms / drug therapy*
  • Pyrazines / administration & dosage
  • Pyrazines / adverse effects
  • Pyrazines / pharmacokinetics
  • Vorinostat
  • Young Adult

Substances

  • Boronic Acids
  • Hydroxamic Acids
  • Pyrazines
  • Vorinostat
  • Bortezomib