A pediatric phase 1 trial of vorinostat and temozolomide in relapsed or refractory primary brain or spinal cord tumors

A children's oncology group phase 1 consortium study

Trent R. Hummel, Lars Wagner, Charlotte Ahern, Maryam Fouladi, Joel M Reid, Renee M. Mcgovern, Matthew M. Ames, Richard J. Gilbertson, Terzah Horton, Ashish M. Ingle, Brenda Weigel, Susan M. Blaney

Research output: Contribution to journalArticle

31 Citations (Scopus)

Abstract

Purpose: We conducted a pediatric phase I study to estimate the maximum tolerated dose (MTD), dose-limiting toxicities (DLT), and pharmacokinetic properties of vorinostat, a histone deacetylase (HDAC) inhibitor, when given in combination with temozolomide in children with refractory or recurrent CNS malignancies. Patients and Methods: Vorinostat, followed by temozolomide approximately 1hour later, was orally administered, once daily, for 5 consecutive days every 28 days at three dose levels using the rolling six design. Studies of histone accumulation in peripheral blood mononuclear cells were performed on Day 1 at 0, 6, and 24hours after vorinostat dosing. Vorinostat pharmacokinetics (PK) and serum MGMT promoter status were also assessed. Results: Nineteen eligible patients were enrolled and 18 patients were evaluable for toxicity. There were no DLTs observed at dose level 1 or 2. DLTs occurred in four patients at dose level 3: thrombocytopenia (4), neutropenia (3), and leucopenia (1). Non-dose limiting grade 3 or 4 toxicities related to protocol therapy were also hematologic and included neutropenia, lymphopenia, thrombocytopenia, anemia, and leucopenia. Three patients exhibited stable disease and one patient had a partial response. There was no clear relationship between vorinostat dosage and drug exposure over the dose range studied. Accumulation of acetylated H3 histone in PBMC was observed after administration of vorinostat. Conclusion: Five-day cycles of vorinostat in combination with temozolomide are well tolerated in children with recurrent CNS malignancies with myelosuppression as the DLT. The recommended phase II combination doses are vorinostat, 300mg/m2/day and temozolomide, 150mg/m2/day.

Original languageEnglish (US)
Pages (from-to)1452-1457
Number of pages6
JournalPediatric Blood and Cancer
Volume60
Issue number9
DOIs
StatePublished - Sep 2013

Fingerprint

temozolomide
Spinal Cord Neoplasms
Pediatrics
Brain
Leukopenia
Neutropenia
Histones
Pharmacokinetics
Lymphopenia
Histone Deacetylase Inhibitors
Maximum Tolerated Dose
vorinostat
Thrombocytopenia

Keywords

  • Children's Oncology Group
  • Pediatric cancer
  • Temozolomide phase I trial
  • Vorinostat

ASJC Scopus subject areas

  • Oncology
  • Pediatrics, Perinatology, and Child Health
  • Hematology

Cite this

A pediatric phase 1 trial of vorinostat and temozolomide in relapsed or refractory primary brain or spinal cord tumors : A children's oncology group phase 1 consortium study. / Hummel, Trent R.; Wagner, Lars; Ahern, Charlotte; Fouladi, Maryam; Reid, Joel M; Mcgovern, Renee M.; Ames, Matthew M.; Gilbertson, Richard J.; Horton, Terzah; Ingle, Ashish M.; Weigel, Brenda; Blaney, Susan M.

In: Pediatric Blood and Cancer, Vol. 60, No. 9, 09.2013, p. 1452-1457.

Research output: Contribution to journalArticle

Hummel, TR, Wagner, L, Ahern, C, Fouladi, M, Reid, JM, Mcgovern, RM, Ames, MM, Gilbertson, RJ, Horton, T, Ingle, AM, Weigel, B & Blaney, SM 2013, 'A pediatric phase 1 trial of vorinostat and temozolomide in relapsed or refractory primary brain or spinal cord tumors: A children's oncology group phase 1 consortium study', Pediatric Blood and Cancer, vol. 60, no. 9, pp. 1452-1457. https://doi.org/10.1002/pbc.24541
Hummel, Trent R. ; Wagner, Lars ; Ahern, Charlotte ; Fouladi, Maryam ; Reid, Joel M ; Mcgovern, Renee M. ; Ames, Matthew M. ; Gilbertson, Richard J. ; Horton, Terzah ; Ingle, Ashish M. ; Weigel, Brenda ; Blaney, Susan M. / A pediatric phase 1 trial of vorinostat and temozolomide in relapsed or refractory primary brain or spinal cord tumors : A children's oncology group phase 1 consortium study. In: Pediatric Blood and Cancer. 2013 ; Vol. 60, No. 9. pp. 1452-1457.
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AU - Wagner, Lars

AU - Ahern, Charlotte

AU - Fouladi, Maryam

AU - Reid, Joel M

AU - Mcgovern, Renee M.

AU - Ames, Matthew M.

AU - Gilbertson, Richard J.

AU - Horton, Terzah

AU - Ingle, Ashish M.

AU - Weigel, Brenda

AU - Blaney, Susan M.

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N2 - Purpose: We conducted a pediatric phase I study to estimate the maximum tolerated dose (MTD), dose-limiting toxicities (DLT), and pharmacokinetic properties of vorinostat, a histone deacetylase (HDAC) inhibitor, when given in combination with temozolomide in children with refractory or recurrent CNS malignancies. Patients and Methods: Vorinostat, followed by temozolomide approximately 1hour later, was orally administered, once daily, for 5 consecutive days every 28 days at three dose levels using the rolling six design. Studies of histone accumulation in peripheral blood mononuclear cells were performed on Day 1 at 0, 6, and 24hours after vorinostat dosing. Vorinostat pharmacokinetics (PK) and serum MGMT promoter status were also assessed. Results: Nineteen eligible patients were enrolled and 18 patients were evaluable for toxicity. There were no DLTs observed at dose level 1 or 2. DLTs occurred in four patients at dose level 3: thrombocytopenia (4), neutropenia (3), and leucopenia (1). Non-dose limiting grade 3 or 4 toxicities related to protocol therapy were also hematologic and included neutropenia, lymphopenia, thrombocytopenia, anemia, and leucopenia. Three patients exhibited stable disease and one patient had a partial response. There was no clear relationship between vorinostat dosage and drug exposure over the dose range studied. Accumulation of acetylated H3 histone in PBMC was observed after administration of vorinostat. Conclusion: Five-day cycles of vorinostat in combination with temozolomide are well tolerated in children with recurrent CNS malignancies with myelosuppression as the DLT. The recommended phase II combination doses are vorinostat, 300mg/m2/day and temozolomide, 150mg/m2/day.

AB - Purpose: We conducted a pediatric phase I study to estimate the maximum tolerated dose (MTD), dose-limiting toxicities (DLT), and pharmacokinetic properties of vorinostat, a histone deacetylase (HDAC) inhibitor, when given in combination with temozolomide in children with refractory or recurrent CNS malignancies. Patients and Methods: Vorinostat, followed by temozolomide approximately 1hour later, was orally administered, once daily, for 5 consecutive days every 28 days at three dose levels using the rolling six design. Studies of histone accumulation in peripheral blood mononuclear cells were performed on Day 1 at 0, 6, and 24hours after vorinostat dosing. Vorinostat pharmacokinetics (PK) and serum MGMT promoter status were also assessed. Results: Nineteen eligible patients were enrolled and 18 patients were evaluable for toxicity. There were no DLTs observed at dose level 1 or 2. DLTs occurred in four patients at dose level 3: thrombocytopenia (4), neutropenia (3), and leucopenia (1). Non-dose limiting grade 3 or 4 toxicities related to protocol therapy were also hematologic and included neutropenia, lymphopenia, thrombocytopenia, anemia, and leucopenia. Three patients exhibited stable disease and one patient had a partial response. There was no clear relationship between vorinostat dosage and drug exposure over the dose range studied. Accumulation of acetylated H3 histone in PBMC was observed after administration of vorinostat. Conclusion: Five-day cycles of vorinostat in combination with temozolomide are well tolerated in children with recurrent CNS malignancies with myelosuppression as the DLT. The recommended phase II combination doses are vorinostat, 300mg/m2/day and temozolomide, 150mg/m2/day.

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