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 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.