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)

• Published in: Pediatric blood & cancer Vol. 60; no. 3; pp. 390 - 395
• Main Authors: Muscal, Jodi A., Thompson, Patrick A., Horton, Terzah M., Ingle, Ashish M., Ahern, Charlotte H., McGovern, Renee M., Reid, Joel M., Ames, Matthew M., Espinoza-Delgado, Igor, Weigel, Brenda J., Blaney, Susan M.
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01-03-2013; Wiley Subscription Services, Inc
• Subjects: Adolescent; Antineoplastic Combined Chemotherapy Protocols - pharmacokinetics; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Boronic Acids - administration & dosage; Boronic Acids - adverse effects; Boronic Acids - pharmacokinetics; Bortezomib; Child; Child, Preschool; Children's Oncology Group; Dose-Response Relationship, Drug; Female; Hematology; Humans; Hydroxamic Acids - administration & dosage; Hydroxamic Acids - adverse effects; Hydroxamic Acids - pharmacokinetics; Infant; Male; Maximum Tolerated Dose; Neoplasms - drug therapy; Oncology; pediatric cancer; Pediatrics; Phase I trial; Pyrazines - administration & dosage; Pyrazines - adverse effects; Pyrazines - pharmacokinetics; solid tumors; vorinostat; Young Adult
• ISSN: 1545-5009; 1545-5017
• DOI: 10.1002/pbc.24271

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/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: 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.
Conclusion
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.