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)

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 15 and 812 of a 21-day cycle (starting dose 180 mg/m2/day with dose escalations to 230 and 300 mg/m2/day). Bortezomib (1.3 mg/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: 120)] 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/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-kappa B 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/m2/day PO on days 15 and 812) in combination with bortezomib (1.3 mg/m2/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. (C) 2012 Wiley Periodicals, Inc.