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

Author:

Appleton Kim1,Mackay Helen J.1,Judson Ian1,Plumb Jane A.1,McCormick Carol1,Strathdee Gordon1,Lee Chooi1,Barrett Sophie1,Reade Sarah1,Jadayel Dalal1,Tang Adrian1,Bellenger Katharine1,Mackay Lynsay1,Setanoians Albert1,Schätzlein Andreas1,Twelves Chris1,Kaye Stanley B.1,Brown Robert1

Affiliation:

1. 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

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.

Publisher

American Society of Clinical Oncology (ASCO)

Subject

Cancer Research,Oncology

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