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Phase I and Pharmacodynamic Trial of the DNA Methyltransferase Inhibitor Decitabine and Carboplatin in Solid Tumors

Kim Appleton, 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

From the Centre for Oncology and Applied Pharmacology, Glasgow University, Cancer Research UK Beatson Laboratories, Glasgow; Cancer Research UK Section of Medicine, Institute of Cancer Research, and Cancer Research UK Centre for Cancer Therapeutics, Institute of Cancer Research, Sutton; Cancer Research UK Drug Development Office, London; Cancer Research UK Clinical Centre, St James's University Hospital, Leeds, United Kingdom

Address reprint requests to Robert Brown, PhD, Cyclotron Building, Hammersmith Hospital Campus, Imperial College, London W12 0NN, United Kingdom. e-mail: b.brown{at}imperial.ac.uk

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.

Supported by Cancer Research UK Grants No. A2662 and DC0024/0201 to R.B.

Presented in part at the 40th Annual Meeting of the American Society of Clinical Oncology, June 5-9, New Orleans, LA; and at the American Association for Cancer Research–National Cancer Institute–European Organisation for Research and Treatment of Cancert International Conference on Molecular Targets and Cancer Therapeutics, November 14-18, 2005, Philadelphia, PA.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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