Phase I study of decitabine with doxorubicin and cyclophosphamide in children with neuroblastoma and other solid tumors

A children's oncology group study

Rani E. George, Jill M. Lahti, Peter C. Adamson, Kejin Zhu, David Finkelstein, A. Mark Ingle, Joel M Reid, Mark Krailo, Donna Neuberg, Susan M. Blaney, Lisa Diller

Research output: Contribution to journalArticle

41 Citations (Scopus)

Abstract

Background: Demethylating agents may alter the expression of genes involved in chemotherapy resistance. We conducted a phase I trial to determine the toxicity and molecular effects of the demethylating agent, decitabine, followed by doxorubicin and cyclophosphamide in children with refractory solid tumors. Procedure: Stratum A included children with any solid tumor; Stratum B included neuroblastoma patients only. Patients received a 1-hr decitabine infusion for 7 days, followed by doxorubicin (45 mg/m2) and cyclophosphamide (1 g/m2) on day 7. Pharmacokinetic studies were performed after the first dose of decitabine. Biological studies included methylation and gene expression analyses of caspase-8, MAGE-1 and fetal hemoglobin (HbF), and expression profiling of pre- and post-treatment peripheral blood and bone marrow cells. Results: The maximum-tolerated dose of decitabine was 5 mg/m2/day for 7 days. Dose-limiting toxicities at 10 mg/m2/day were neutropenia and thrombocytopenia. Decitabine exhibited rapid clearance from plasma. Three of 9 patients in Stratum A and 4/12 patients in Stratum B had stable disease for ≥4 months. Sustained MAGE-1 demethylation and increased HbF expression were observed in the majority of patients post-treatment (12/20 and 14/16, respectively). Caspase-8 promoter demethylation and gene expression were seen in 2/7 bone marrow samples. Differentially expressed genes were identified by microarray analysis. Conclusion: Low-dose decitabine when combined with doxorubicin/cyclophosphamide has tolerable toxicity in children. However, doses of decitabine capable of producing clinically relevant biologic effects were not well tolerated with this combination. Alternative strategies of combining demethylating agents with non-cytotoxic, biologically targeted agents such as histone deactelyase inhibitors should be explored. Pediatr Blood Cancer.

Original languageEnglish (US)
Pages (from-to)629-638
Number of pages10
JournalPediatric Blood and Cancer
Volume55
Issue number4
DOIs
StatePublished - Oct 2010

Fingerprint

decitabine
Neuroblastoma
Doxorubicin
Cyclophosphamide
Neoplasms
Caspase 8
Gene Expression
Fetal Hemoglobin
Maximum Tolerated Dose
Microarray Analysis
Neutropenia
Bone Marrow Cells
Thrombocytopenia
Histones
Methylation
Therapeutics

Keywords

  • Decitabine
  • Demethylation
  • Neuroblastoma
  • Pediatric solid tumor

ASJC Scopus subject areas

  • Oncology
  • Pediatrics, Perinatology, and Child Health
  • Hematology
  • Medicine(all)

Cite this

Phase I study of decitabine with doxorubicin and cyclophosphamide in children with neuroblastoma and other solid tumors : A children's oncology group study. / George, Rani E.; Lahti, Jill M.; Adamson, Peter C.; Zhu, Kejin; Finkelstein, David; Ingle, A. Mark; Reid, Joel M; Krailo, Mark; Neuberg, Donna; Blaney, Susan M.; Diller, Lisa.

In: Pediatric Blood and Cancer, Vol. 55, No. 4, 10.2010, p. 629-638.

Research output: Contribution to journalArticle

George, RE, Lahti, JM, Adamson, PC, Zhu, K, Finkelstein, D, Ingle, AM, Reid, JM, Krailo, M, Neuberg, D, Blaney, SM & Diller, L 2010, 'Phase I study of decitabine with doxorubicin and cyclophosphamide in children with neuroblastoma and other solid tumors: A children's oncology group study', Pediatric Blood and Cancer, vol. 55, no. 4, pp. 629-638. https://doi.org/10.1002/pbc.22607
George, Rani E. ; Lahti, Jill M. ; Adamson, Peter C. ; Zhu, Kejin ; Finkelstein, David ; Ingle, A. Mark ; Reid, Joel M ; Krailo, Mark ; Neuberg, Donna ; Blaney, Susan M. ; Diller, Lisa. / Phase I study of decitabine with doxorubicin and cyclophosphamide in children with neuroblastoma and other solid tumors : A children's oncology group study. In: Pediatric Blood and Cancer. 2010 ; Vol. 55, No. 4. pp. 629-638.
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abstract = "Background: Demethylating agents may alter the expression of genes involved in chemotherapy resistance. We conducted a phase I trial to determine the toxicity and molecular effects of the demethylating agent, decitabine, followed by doxorubicin and cyclophosphamide in children with refractory solid tumors. Procedure: Stratum A included children with any solid tumor; Stratum B included neuroblastoma patients only. Patients received a 1-hr decitabine infusion for 7 days, followed by doxorubicin (45 mg/m2) and cyclophosphamide (1 g/m2) on day 7. Pharmacokinetic studies were performed after the first dose of decitabine. Biological studies included methylation and gene expression analyses of caspase-8, MAGE-1 and fetal hemoglobin (HbF), and expression profiling of pre- and post-treatment peripheral blood and bone marrow cells. Results: The maximum-tolerated dose of decitabine was 5 mg/m2/day for 7 days. Dose-limiting toxicities at 10 mg/m2/day were neutropenia and thrombocytopenia. Decitabine exhibited rapid clearance from plasma. Three of 9 patients in Stratum A and 4/12 patients in Stratum B had stable disease for ≥4 months. Sustained MAGE-1 demethylation and increased HbF expression were observed in the majority of patients post-treatment (12/20 and 14/16, respectively). Caspase-8 promoter demethylation and gene expression were seen in 2/7 bone marrow samples. Differentially expressed genes were identified by microarray analysis. Conclusion: Low-dose decitabine when combined with doxorubicin/cyclophosphamide has tolerable toxicity in children. However, doses of decitabine capable of producing clinically relevant biologic effects were not well tolerated with this combination. Alternative strategies of combining demethylating agents with non-cytotoxic, biologically targeted agents such as histone deactelyase inhibitors should be explored. Pediatr Blood Cancer.",
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AU - Adamson, Peter C.

AU - Zhu, Kejin

AU - Finkelstein, David

AU - Ingle, A. Mark

AU - Reid, Joel M

AU - Krailo, Mark

AU - Neuberg, Donna

AU - Blaney, Susan M.

AU - Diller, Lisa

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AB - Background: Demethylating agents may alter the expression of genes involved in chemotherapy resistance. We conducted a phase I trial to determine the toxicity and molecular effects of the demethylating agent, decitabine, followed by doxorubicin and cyclophosphamide in children with refractory solid tumors. Procedure: Stratum A included children with any solid tumor; Stratum B included neuroblastoma patients only. Patients received a 1-hr decitabine infusion for 7 days, followed by doxorubicin (45 mg/m2) and cyclophosphamide (1 g/m2) on day 7. Pharmacokinetic studies were performed after the first dose of decitabine. Biological studies included methylation and gene expression analyses of caspase-8, MAGE-1 and fetal hemoglobin (HbF), and expression profiling of pre- and post-treatment peripheral blood and bone marrow cells. Results: The maximum-tolerated dose of decitabine was 5 mg/m2/day for 7 days. Dose-limiting toxicities at 10 mg/m2/day were neutropenia and thrombocytopenia. Decitabine exhibited rapid clearance from plasma. Three of 9 patients in Stratum A and 4/12 patients in Stratum B had stable disease for ≥4 months. Sustained MAGE-1 demethylation and increased HbF expression were observed in the majority of patients post-treatment (12/20 and 14/16, respectively). Caspase-8 promoter demethylation and gene expression were seen in 2/7 bone marrow samples. Differentially expressed genes were identified by microarray analysis. Conclusion: Low-dose decitabine when combined with doxorubicin/cyclophosphamide has tolerable toxicity in children. However, doses of decitabine capable of producing clinically relevant biologic effects were not well tolerated with this combination. Alternative strategies of combining demethylating agents with non-cytotoxic, biologically targeted agents such as histone deactelyase inhibitors should be explored. Pediatr Blood Cancer.

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