Phase I and pharmacodynamic trial of the DNA methyltransferase inhibitor decitabine and carboplatin in solid tumors - PubMed (original) (raw)

Clinical Trial

. 2007 Oct 10;25(29):4603-9.

doi: 10.1200/JCO.2007.10.8688.

Helen J Mackay, Ian Judson, Jane A Plumb, Carol McCormick, Gordon Strathdee, Chooi Lee, Sophie Barrett, Sarah Reade, Dalal Jadayel, Adrian Tang, Katharine Bellenger, Lynsay Mackay, Albert Setanoians, Andreas Schätzlein, Chris Twelves, Stanley B Kaye, Robert Brown

Affiliations

Clinical Trial

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

Kim Appleton et al. J Clin Oncol. 2007.

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.

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