A Phase I Study of Intravenous Decitabine in Combination With Arsenic Trioxide and Ascorbic Acid in Patients With Myelodysplastic Syndromes and Acute Myeloid Leukemia
Myelodysplastic syndromes (MDS) are hematological disorders characterized by ineffective
hematopoiesis. DNA hypomethylating agents such as decitabine have been shown to have
activity in this disorder by reversing the epigenetic mechanism of gene silencing.
Acute Myeloid Leukemia (AML) is a hematological disorder characterized by ineffective
hematopoiesis and malignant expansion of clonal myeloid cells. In elderly patients (≥ 60
years old), MDS commonly precedes the diagnosis of AML. Standard therapy for AML consists of
cytotoxic chemotherapy and is often followed with allogeneic stem cell transplantation.
Unfortunately, elderly patients are often unable to tolerate such aggressive therapy.
Arsenic has also shown activity in patients with MDS and AML though modulation of apoptosis
via increased oxidative stress. In preclinical modes, arsenic activity is related to the
production of radical oxygen species that damage mitochondria. Cellular glutathione acts as
a cellular antioxidant and can be depleted with the vitamin ascorbic acid which increases
intracellular oxidative stress and sensitivity to arsenic trioxide induced apoptosis.
We are studying the combination of decitabine, arsenic trioxide and ascorbic acid, two
primary agents and one vitamin all with different mechanisms of action in order to improve
the response rate in patients with MDS and AML. This is an open-label, single-arm,
single-center, dose escalation Phase I trial of decitabine, arsenic trioxide and ascorbic
acid in patients with MDS, either de novo or secondary, fitting any of the FAB
classifications and AML.
Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
To define the maximum tolerated dose and dose-limiting toxicities during four cycles of combination decitabine, arsenic trioxide and ascorbic acid in patients with myelodysplastic syndromes (MDS) previously untreated with hypomethylating agents.
4 months after the final patient on the final cohort starts treatment
Ravi Vij, M.D.
United States: Food and Drug Administration
07-0916 / 201011797
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