Conflicts of interest: Nothing to declare.
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)†
Article first published online: 9 AUG 2012
Copyright © 2012 Wiley Periodicals, Inc.
Pediatric Blood & Cancer
Volume 60, Issue 3, pages 390–395, March 2013
How to Cite
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. and 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). Pediatr. Blood Cancer, 60: 390–395. doi: 10.1002/pbc.24271
- Issue published online: 15 JAN 2013
- Article first published online: 9 AUG 2012
- Manuscript Accepted: 3 JUL 2012
- Manuscript Received: 16 MAR 2012
- National Cancer Institute (NCI) Phase I/Pilot Consortium. Grant Number: U01 CA97452
- NCI Pediatric Clinical Oncology Research Training Program. Grant Number: 5K12CA90433-09
- Kappa Alpha Theta Research Scholar Award
- Carousel Faculty Research Scholar Award
- Children's Oncology Group;
- pediatric cancer;
- Phase I trial;
- solid tumors;
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.
Oral vorinostat was administered on days 1–5 and 8–12 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.
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/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.
The recommended Phase 2 dose and schedule is vorinostat (230 mg/m2/day PO on days 1–5 and 8–12) 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. © 2012 Wiley Periodicals, Inc.