A phase I trial of veliparib (ABT-888) and temozolomide in children with recurrent CNS tumors: A pediatric brain tumor consortium report

Jack M. Su, Patrick Thompson, Adekunle Adesina, Xiao Nan Li, Lindsay Kilburn, Arzu Onar-Thomas, Mehmet Kocak, Brenda Chyla, Evelyn McKeegan, Katherine E. Warren, Stewart Goldman, Ian F. Pollack, Maryam Fouladi, Alice Chen, Vincent Giranda, James Boyett, Larry Kun, Susan M. Blaney

Research output: Contribution to journalArticle

34 Scopus citations

Abstract

Background: A phase I trial of veliparib (ABT-888), an oral poly(ADP-ribose) polymerase (PARP) inhibitor, and temozolomide (TMZ) was conducted in children with recurrent brain tumors to (i) estimate the maximum tolerated doses (MTDs) or recommended phase II doses (RP2Ds) of veliparib and TMZ; (ii) describe the toxicities of this regimen; and (iii) evaluate the plasma pharmacokinetic parameters and extent of PARP inhibition in peripheral blood mononuclear cells (PBMCs) following veliparib. Methods: TMZ was given once daily and veliparib twice daily for 5 days every 28 days. Veliparib concentrations and poly(ADP-ribose) (PAR) levels in PBMCs were measured on days 1 and 4. Analysis of pharmacokinetic and PBMC PAR levels were performed twice during study conduct to rationally guide dose modifications and to determine biologically optimal MTD/RP2D. Results: Twenty-nine evaluable patients were enrolled. Myelosuppression (grade 4 neutropenia and thrombocytopenia) were dose limiting. The RP2Ds are veliparib 25 mg/m2 b.i.d. and TMZ 135 mg/m2/d. Only 2 out of 12 patients treated at RP2Ds experienced dose-limiting toxicities. Although no objective response was observed, 4 patients had stable disease.6 months in duration, including 1 with glioblastoma multiforme and 1 with ependymoma. At the RP2D of veliparib, pediatric pharmacokinetic parameters were similar to those in adults. Conclusions: Veliparib and TMZ at the RP2D werewell tolerated in children with recurrent brain tumors. A phase I/II trial to evaluate the tolerability and efficacy of veliparib, TMZ, and radiation in children with newly diagnosed brainstem gliomas is in progress.

Original languageEnglish (US)
Pages (from-to)1661-1668
Number of pages8
JournalNeuro-oncology
Volume16
Issue number12
DOIs
StatePublished - Jan 1 2014

Keywords

  • ABT-888
  • CNS tumors
  • PARP inhibition
  • Pediatric phase I study
  • Veliparib

ASJC Scopus subject areas

  • Oncology
  • Clinical Neurology
  • Cancer Research

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    Su, J. M., Thompson, P., Adesina, A., Li, X. N., Kilburn, L., Onar-Thomas, A., Kocak, M., Chyla, B., McKeegan, E., Warren, K. E., Goldman, S., Pollack, I. F., Fouladi, M., Chen, A., Giranda, V., Boyett, J., Kun, L., & Blaney, S. M. (2014). A phase I trial of veliparib (ABT-888) and temozolomide in children with recurrent CNS tumors: A pediatric brain tumor consortium report. Neuro-oncology, 16(12), 1661-1668. https://doi.org/10.1093/neuonc/nou103