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.

• Authors: Jodi A Muscal, Patrick A Thompson, Terzah M Horton, Ashish M Ingle, Charlotte H Ahern, Renee M McGovern, Joel M Reid, Matthew M Ames, Igor Espinoza-Delgado, Brenda J Weigel, Susan M Blaney
• Journal: Pediatric blood & cancer (Pediatr Blood Cancer) Vol. 60 Issue 3 Pg. 390-5 (Mar 2013) ISSN: 1545-5017 [Electronic] United States
• PMID: 22887890 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 Wiley Periodicals, Inc.

Chemical References

• Boronic Acids
• Endoplasmic Reticulum Chaperone BiP
• HSPA5 protein, human
• Hydroxamic Acids
• Pyrazines
• Vorinostat
• Bortezomib

Topics

• Adolescent
• Antineoplastic Combined Chemotherapy Protocols (pharmacokinetics, therapeutic use)
• Boronic Acids (administration & dosage, adverse effects, pharmacokinetics)
• Bortezomib
• Child
• Child, Preschool
• Dose-Response Relationship, Drug
• Endoplasmic Reticulum Chaperone BiP
• Female
• Humans
• Hydroxamic Acids (administration & dosage, adverse effects, pharmacokinetics)
• Infant
• Male
• Maximum Tolerated Dose
• Neoplasms (drug therapy)
• Pyrazines (administration & dosage, adverse effects, pharmacokinetics)
• Vorinostat
• Young Adult