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).

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 180 mg/m(2) /day with dose escalations to 230 and 300 mg/m(2) /day). Bortezomib (1.3 mg/m(2) 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 300 mg/m(2) /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 (230 mg/m(2) /day PO on days 1-5 and 8-12) in combination with bortezomib (1.3 mg/m(2) /day i.v. on days 1, 4, 8, and 11 of a 21-day cycle) in children with recurrent or refractory solid tumors.

journal_name

Pediatr Blood Cancer

journal_title

Pediatric blood & cancer

authors

Muscal JA,Thompson PA,Horton TM,Ingle AM,Ahern CH,McGovern RM,Reid JM,Ames MM,Espinoza-Delgado I,Weigel BJ,Blaney SM

doi

10.1002/pbc.24271

subject

Has Abstract

pub_date

2013-03-01 00:00:00

pages

390-5

issue

3

eissn

1545-5009

issn

1545-5017

journal_volume

60

pub_type

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