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

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)

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  • Medientyp: E-Artikel
  • Titel: 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)
  • Beteiligte: Muscal, Jodi A.; Thompson, Patrick A.; Horton, Terzah M.; Ingle, Ashish M.; Ahern, Charlotte H.; McGovern, Renee M.; Reid, Joel M.; Ames, Matthew M.; Espinoza‐Delgado, Igor; Weigel, Brenda J.; Blaney, Susan M.
  • Erschienen: Wiley, 2013
  • Erschienen in: Pediatric Blood & Cancer
  • Sprache: Englisch
  • DOI: 10.1002/pbc.24271
  • ISSN: 1545-5009; 1545-5017
  • Schlagwörter: Oncology ; Hematology ; Pediatrics, Perinatology and Child Health
  • Entstehung:
  • Anmerkungen:
  • Beschreibung: <jats:title>Abstract</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>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.</jats:p></jats:sec><jats:sec><jats:title>Procedure</jats:title><jats:p>Oral vorinostat was administered on days 1–5 and 8–12 of a 21‐day cycle (starting dose 180 mg/m<jats:sup>2</jats:sup>/day with dose escalations to 230 and 300 mg/m<jats:sup>2</jats:sup>/day). Bortezomib (1.3 mg/m<jats:sup>2</jats:sup> 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.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>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<jats:sup>2</jats:sup>/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.</jats:p></jats:sec><jats:sec><jats:title>Conclusion</jats:title><jats:p>The recommended Phase 2 dose and schedule is vorinostat (230 mg/m<jats:sup>2</jats:sup>/day PO on days 1–5 and 8–12) in combination with bortezomib (1.3 mg/m<jats:sup>2</jats:sup>/day i.v. on days 1, 4, 8, and 11 of a 21‐day cycle) in children with recurrent or refractory solid tumors. Pediatr Blood Cancer 2013; 60: 390–395. © 2012 Wiley Periodicals, Inc.</jats:p></jats:sec>