title: Phase I study of decitabine with doxorubicin and cyclophosphamide in children with neuroblastoma and other solid tumors: a Children's Oncology Group study.
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.
  
  
  METHODS
  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/m(2)) and cyclophosphamide (1 g/m(2)) 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/m(2)/day for 7 days. Dose-limiting toxicities at 10 mg/m(2)/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 > or = 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.
  
  
  CONCLUSIONS
  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 deacetylase inhibitors should be explored.
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute and Children's Hospital, Boston, Massachusetts 02115, USA. rani george@dfci.harvard.edu
authors.forename: Rani E
authors.initials: RE
authors.lastname: George
authors.forename: Jill M
authors.initials: JM
authors.lastname: Lahti
authors.forename: Peter C
authors.initials: PC
authors.lastname: Adamson
authors.forename: Kejin
authors.initials: K
authors.lastname: Zhu
authors.forename: David
authors.initials: D
authors.lastname: Finkelstein
authors.forename: A Mark
authors.initials: AM
authors.lastname: Ingle
authors.forename: Joel M
authors.initials: JM
authors.lastname: Reid
authors.forename: Mark
authors.initials: M
authors.lastname: Krailo
authors.forename: Donna
authors.initials: D
authors.lastname: Neuberg
authors.forename: Susan M
authors.initials: SM
authors.lastname: Blaney
authors.forename: Lisa
authors.initials: L
authors.lastname: Diller
mesh_terms: D000293:Adolescent; D000328:Adult; D000951:Antigens, Neoplasm / Q000235:genetics; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001374:Azacitidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D053181:Caspase 8 / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D019175:DNA Methylation; D000077209:Decitabine; D004317:Doxorubicin / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D005260:Female; D005319:Fetal Hemoglobin / Q000235:genetics; D020869:Gene Expression Profiling; D006801:Humans; D007223:Infant; D008297:Male; D058950:Melanoma-Specific Antigens; D009363:Neoplasm Proteins / Q000235:genetics; D009369:Neoplasms / Q000188:drug therapy*; D009447:Neuroblastoma / Q000188:drug therapy*
chemical_list: D000951:Antigens, Neoplasm; C072011:MAGEA1 protein, human; D058950:Melanoma-Specific Antigens; D009363:Neoplasm Proteins; D000077209:Decitabine; D004317:Doxorubicin; D003520:Cyclophosphamide; D005319:Fetal Hemoglobin; D053181:Caspase 8; D001374:Azacitidine