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)

Jodi A. Muscal, Patrick A. Thompson, Terzah M. Horton, Ashish M. Ingle, Charlotte H. Ahern, Renee M. McGovern, Joel M. Reid, Matthew M. Ames, Igor Espinoza-Delgado, Brenda J. Weigel, Susan M. Blaney

Research output: Contribution to journalArticle

45 Scopus citations

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 180mg/m2/day with dose escalations to 230 and 300mg/m2/day). Bortezomib (1.3mg/m2 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 300mg/m2/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 (230mg/m2/day PO on days 1-5 and 8-12) in combination with bortezomib (1.3mg/m2/day i.v. on days 1, 4, 8, and 11 of a 21-day cycle) in children with recurrent or refractory solid tumors.

Original languageEnglish (US)
Pages (from-to)390-395
Number of pages6
JournalPediatric Blood and Cancer
Volume60
Issue number3
DOIs
StatePublished - Mar 1 2013

Keywords

  • Bortezomib
  • Children's Oncology Group
  • Pediatric cancer
  • Phase I trial
  • Solid tumors
  • Vorinostat

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health
  • Hematology
  • Oncology

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    Muscal, J. A., Thompson, P. A., Horton, T. M., Ingle, A. M., Ahern, C. H., McGovern, R. M., Reid, J. M., Ames, M. M., Espinoza-Delgado, I., Weigel, B. J., & Blaney, S. M. (2013). 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). Pediatric Blood and Cancer, 60(3), 390-395. https://doi.org/10.1002/pbc.24271