Phase I Study of Decitabine With Doxorubicin and Cyclophosphamide in Children With Neuroblastoma and Other Solid Tumors: A Children's Oncology Group Study

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/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)/clay for 7 days Dose-limiting toxicities at 10 mg/m(2)/clay 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 2010,55 629-638 (C) 2010 Wiley-Liss, Inc