Phase I Study of Decitabine (Dacogen) and Bortezomib (Velcade) in Acute Myeloid Leukemia
I. To determine the maximum tolerated dose (MTD) of bortezomib (Velcade, PS-341) in
combination with decitabine in patients with acute myeloid leukemia (AML) II. To define the
specific toxicities and the dose limiting toxicity (DLT) of decitabine plus bortezomib
I. To determine the overall response rate (ORR). II. To determine the rate of complete
remission (CR) of decitabine plus bortezomib in AML III. To correlate the biological
activity of decitabine as demethylating agent (changes in target gene methylation and gene
expression, DNMT1 protein expression, global methylation) with clinical endpoints and plasma
pharmacokinetics of decitabine.
IV. To characterize the biological activity of bortezomib as a potential demethylating agent
V. To correlate intracellular concentration of decitabine-triphosphate with global DNA
methylation and other biological endpoints as well as clinical response.
VI. To explore the biologic role of microRNAs in determining clinical response to the
decitabine plus bortezomib combination and achievement of the other pharmacodynamic
OUTLINE: This is a dose-escalation study of bortezomib.
Patients receive decitabine intravenously (IV) over 1 hour on days 1-5 or 1-10 and
bortezomib IV on days 5 and 8 or days 5, 8, 12, and 15. Courses repeat every 28 days in the
absence of disease progression or unacceptable toxicity. Once the maximum tolerated dose is
determined, an additional 6 patients are treated at the recommended phase II dose.
After completion of study treatment, patients are followed for at least 30 days.
Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Maximum-tolerated dose (MTD) of bortezomib in combination with decitabine
If a patient meets the definition of dose-limiting toxicity (DLT), the patient may continue on with study therapy provided that the toxicity can be managed according to the dose modification guidelines. For DLT = 2, dose level will stop. This dose level will be declared the MTD administered dose (highest dose administered). As an exploratory, phase I study, no inferential statistical tests of hypotheses are planned. Data collected will be descriptive and provide limited estimates of variability given the small sample sizes at each dose level.
During course 1 (28 days)
Ohio State University
United States: Food and Drug Administration
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