with chemotherapy are under way in various malignancies.25 We recently initiated a phase I/II AZD2171 study of the cyclophosphamide, doxorubicin, and cisplatin regimen plus belinostat in patients with advanced thymic malignancies who have not received prior chemotherapy .The inhibition of histone deacetylase can induce differentiation, growth arrest, and apoptosis in cancer cells. This phase II multicenter study was undertaken to estimate the efficacy of belinostat, a potent inhibitor of both class I and class II HDAC enzymes, for the treatment of myelodysplastic syndrome . Adults with MDS and ≤2 prior therapies were treated with belinostat 1,000 mg/m2 IV on days 15 of a 21 day cycle. The primary endpoint was a proportion of confirmed responses during the first 12 weeks of treatment.
Responding patients could receive additional cycles until disease progression or unacceptable toxicity. Twenty one patients were enrolled, and all were evaluable. Patients were a median 13.4 months from diagnosis, nebivolol molecular weight and 14 patients Doripenem price had less than 5% bone marrow blasts. Seventeen patients were transfusion dependent. Prior therapy included azacytidine and chemotherapy . The patients were treated with a median of four cycles of belinostat. There was one confirmed response hematologic improvement in neutrophils for an overall response rate of 5% . Median overall survival was 17.9 months. Grades 34 toxicities considered at least to be possibly related to belinostat were: neutropenia , thrombocytopenia , anemia , fatigue , febrile neutropenia , headache , and QTc prolongation .
Because the study met the stopping rule in the first stage of enrollment, it was closed to further accrual.MDS are the DNA methyltransferase Gemcitabine Antimetabolites inhibitor inhibitors decitabine and azacytidine, which alter methylation patterns on DNA, leading to changes in gene expression and cellular differentiation. Histone deacetylase inhibitors also exert their activity via epigenetic changes in malignant cells, by promoting acetylation of histones and thereby, altering nucleosome and chromatin structure. Pre clinical studies have shown the HDAC inhibitors induce differentiation in leukemic cell lines and in leukemia cells collected from acute myeloid leukemia patients . Multiple HDAC inhibitors have been studied in MDS and AML, with activity observed in phase I and II studies .
Belinostat is a potent inhibitor of both classes I and II HDAC enzymes, and in vitro studies have demonstrated its ability to inhibit growth and promote apoptosis in cancer cell lines . A phase I study in patients with advanced solid tumors demonstrated hyperacetylation of histone H4 that was sustained for 424 h after each dose of belinostat carbohydrates . That study established a maximum tolerated dose of 1,000 mg/m2 daily for 5 days of a 21 day cycle, with dose limiting toxicities of fatigue, atrial fibrillation, diarrhea, nausea, and vomiting. No significant myelosuppression was observed. A similar toxicity profile was observed in a phase I study of belinostat in patients with advanced hematologic malignancies, with the exception that no cardiac events occurred. There was only one case of grades 34 hematologic toxicity over baseline. This multicenter phase II study was undertaken to estimate the efficacy and the toxicity of belinostat in patients with MDS.