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

doi:10.1093/neuonc/nou103

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

^*Corresponding author for this work

Pediatrics

Research output: Contribution to journal › Article › peer-review

60 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 language	English (US)
Pages (from-to)	1661-1668
Number of pages	8
Journal	Neuro-oncology
Volume	16
Issue number	12
DOIs	https://doi.org/10.1093/neuonc/nou103
State	Published - Dec 2014

Keywords

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

ASJC Scopus subject areas

Clinical Neurology
Oncology
Cancer Research

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1093/neuonc/nou103

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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

@article{e6c5c3e0dd28424caab39adba87c2067,

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

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.",

keywords = "ABT-888, CNS tumors, PARP inhibition, Pediatric phase I study, Veliparib",

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

note = "Publisher Copyright: {\textcopyright} The Author(s) 2014.",

year = "2014",

month = dec,

doi = "10.1093/neuonc/nou103",

language = "English (US)",

volume = "16",

pages = "1661--1668",

journal = "Neuro-oncology",

issn = "1522-8517",

publisher = "Oxford University Press",

number = "12",

}

Su, JM, Thompson, P, Adesina, A, Li, XN, Kilburn, L, Onar-Thomas, A, Kocak, M, Chyla, B, McKeegan, E, Warren, KE, Goldman, S, Pollack, IF, Fouladi, M, Chen, A, Giranda, V, Boyett, J, Kun, L & Blaney, SM 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, vol. 16, no. 12, pp. 1661-1668. https://doi.org/10.1093/neuonc/nou103

TY - JOUR

T1 - A phase I trial of veliparib (ABT-888) and temozolomide in children with recurrent CNS tumors

T2 - A pediatric brain tumor consortium report

AU - Su, Jack M.

AU - Thompson, Patrick

AU - Adesina, Adekunle

AU - Li, Xiao Nan

AU - Kilburn, Lindsay

AU - Onar-Thomas, Arzu

AU - Kocak, Mehmet

AU - Chyla, Brenda

AU - McKeegan, Evelyn

AU - Warren, Katherine E.

AU - Goldman, Stewart

AU - Pollack, Ian F.

AU - Fouladi, Maryam

AU - Chen, Alice

AU - Giranda, Vincent

AU - Boyett, James

AU - Kun, Larry

AU - Blaney, Susan M.

PY - 2014/12

Y1 - 2014/12

N2 - 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.

AB - 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.

KW - ABT-888

KW - CNS tumors

KW - PARP inhibition

KW - Pediatric phase I study

KW - Veliparib

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UR - http://www.scopus.com/inward/citedby.url?scp=84925969599&partnerID=8YFLogxK

U2 - 10.1093/neuonc/nou103

DO - 10.1093/neuonc/nou103

M3 - Article

C2 - 24908656

AN - SCOPUS:84925969599

SN - 1522-8517

VL - 16

SP - 1661

EP - 1668

JO - Neuro-oncology

JF - Neuro-oncology

IS - 12

ER -

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

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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