Phase I and pharmacodynamic trial of the DNA methyltransferase inhibitor decitabine and carboplatin in solid tumors

Appleton, K. et al. (2007) Phase I and pharmacodynamic trial of the DNA methyltransferase inhibitor decitabine and carboplatin in solid tumors. Journal of Clinical Oncology, 25(29), pp. 4603-4609. (doi: 10.1200/JCO.2007.10.8688)

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Abstract

Purpose The DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine (decitabine) induces DNA demethylation and re-expression of epigenetically silenced genes, and increases carboplatin sensitivity of tumor xenograft models. We designed a clinical study to determine the feasibility of delivering a dose of decitabine, combined with carboplatin, that would be capable of producing equivalent biologic effects in patients with solid tumors. Patients and Methods In a two-stage design, 33 patients received escalating doses of decitabine administered as a 6-hour infusion on day 1 followed by carboplatin, area under the concentration-time curve (AUC) 5 (cohort 1) and AUC 6 (cohort 2), on day 8 of a 28-day cycle. Pharmacodynamic analyses included 5-methyl-2'-deoxycytidine levels, MAGE1A CpG island methylation, and fetal hemoglobin (HbF) expression. Results The major toxicity was myelosuppression. Dose limiting toxicities, prolonged grade 4 neutropenia (one patient), and sepsis and grade 3 anorexia/fatigue (one patient), were seen in two of four patients treated with decitabine 135 mg/m2 and carboplatin AUC 5. Dose limiting toxicity comprising neutropenic sepsis (one patient) and grade 3 fatigue (one patient) was seen in two of 10 patients treated at decitabine 90 mg/m2 and carboplatin AUC 6. Decitabine induced dose-dependent, reversible demethylation in peripheral-blood cells (PBCs) maximally at day 10. Furthermore, decitabine 90 mg/m2 induced demethylation of the MAGE1A CpG island in PBCs, buccal cells, and tumor biopsies, as well as elevation of HbF expression. Conclusion Decitabine can be combined safely with carboplatin at a dose and schedule that causes epigenetic changes equivalent to or greater than that observed in mice with carboplatin-sensitized xenografts. The recommended dose/schedule for phase II trials is decitabine 90 mg/m2 (day 1) followed by carboplatin AUC 6 (day 8) every 28 days

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Plumb, Dr Jane and Appleton, Ms Kim and Setanoians, Mr Albert and Brown, Prof Robert and McCormick, Mrs Carol and MacKay, Miss Lynsay
Authors: Appleton, K., Mackay, H.J., Judson, I., Plumb, J., McCormick, C., Strathdee, G., Lee, C., Barrett, S., Reade, S., Jadayel, D., Tang, A., Bellenger, K., MacKay, L., Setanoians, A., Schatzlein, A., Twelves, C., Kaye, S.B., and Brown, R.
College/School:College of Medical Veterinary and Life Sciences > Institute of Health and Wellbeing > Mental Health and Wellbeing
College of Medical Veterinary and Life Sciences
Journal Name:Journal of Clinical Oncology
Journal Abbr.:J. Clin. Oncol.
ISSN:0732-183X
ISSN (Online):1527-7755

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