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Title: Early Phase 1 Trial of Decitabine Suggests a Low Dose May Reduce DNA Mediation in Cancer Patients: Presented at AACR-NCI-EORTC

"Early Phase 1 Trial of Decitabine Suggests a Low Dose May Reduce DNA Mediation in Cancer Patients: Presented at AACR-NCI-EORTC"

By Maggie Schwarz PHILADELPHIA, PA -- November 18, 2005 -- Low-dose decitabine is well tolerated in heavily pretreated patients with cancer, according to early research presented here at the International Conference on Molecular Targets and Cancer Therapeutics. The conference was organized jointly by the American Association for Cancer Research - National Cancer Institute - European Organisation for Research and Treatment of Cancer (AACR-NCI-EORTC). Luis Camacho, MD, MPH, Assistant Professor, Melanoma Medical Oncology, Phase I Clinical Trials Program, M.D. Anderson Cancer Center, Houson, Texas, United States, and colleagues undertook the trial to define maximum tolerated dose and assess if there is a biologically optimal dose at which effect on DNA methylation plateaus. The study so far has six patients per dose level, and planned daily dose levels of 2.5 mg/m[², 5 mg/m², 10 mg/m², 15 mg/m² and 20 mg/m².

By inhibiting DNA methyltransferase and decreasing DNA methylation, decitabine may upregulate expression of tumor suppressor genes and pro-apoptotic genes that are silenced by hypermethylation, Dr. Camacho speculated.

Prolonged therapy with decitabine might be more effective than short courses. In treatment of leukemia, efficacy of IV decitabine over 1 hour per day, 5 days per week, 2-week plateaus as with increasing doses, as does DNA demethylation. The optimal dose is approximately 15 mg/m² per day on this schedule.

Twelve patients have been entered in the study so far, with six patients each on cohorts 1 (2.5 mg/m² per day) and 2 (5 mg/m² per day).

Results so far show no dose-limiting toxicity in cohort 1, and a heavily pretreated patient with cutaneous T-cell lymphoma experienced a minor response, Dr. Camacho reported.

The toxicity and efficacy evaluations are not yet complete in cohort 2.

Pre- and post-treatment biopsies and peripheral blood mononuclear cells (PBMCs) have been obtained from all 12 patients, and cohort 1 samples have been assayed.

Tumor DNA methylation decreased by 5% to 15% in three of six cohort 1 patients. Peripheral blood mononuclear cell (PBMC) DNA methylation decreased in all six patients by 3% to 23%. Baseline methylation was higher in PBMCs than tumor. The percent change in DNA methylation post- decitabine in tumor correlated with that in PBMCs (r2 = 0.4).

These initial results suggest that low-dose decitabine may reduce DNA methylation in cancer patients, with the impact on PBMC DNA being greater than on tumor DNA, Dr. Camacho said.

"It's encouraging to see DNA hypomethylation by decitabine occurs even at the lowest dose tested," he concluded.

The research group plans to move forward with studies on decitabine, he said.

[Presentation title: Phase I/Pharmacodynamic Study of Decitabine 5 Days/Week x 2 Weeks in Advanced Cancers. Abstract B130]

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