Phase I Study of Vidaza and Velcade (Bortezomib) in Acute Myeloid Leukemia
- To determine the maximum tolerated dose (MTD) bortezomib in combination with
Azacytidine in patients with relapsed/refractory acute myeloid leukemia (AML) and
myelodysplastic syndromes (MDS).
- To define the specific toxicities and the dose limiting toxicity (DLT) of Azacytidine
plus bortezomib combination.
- To determine the overall response rate (ORR).
- To determine the rate of complete remission (CR) of Azacytidine plus bortezomib in
relapsed/refractory AML and MDS.
- To correlate the biological activity of Azacytidine as demethylating agent (changes in
target gene methylation and gene expression, DNMT1 protein expression, global
methylation) with clinical endpoints and plasma pharmacokinetics of azacytidine.
- To characterize the biological activity of bortezomib as a potential demethylating
- To correlate intracellular concentration of azacytidine-triphosphate with global DNA
methylation and other biological endpoints as well as clinical response.
- To explore the biologic role of microRNAs in determining clinical response to the
azacytidine plus bortezomib combination and achievement of the other pharmacodynamic
OUTLINE: This is a dose-escalation study of bortezomib.
Patients receive azacytidine IV over 30 minutes on days 1-7 and bortezomib IV on days 2 and
5 or on days 2, 5, and 9 or on days 2, 5, 9, and 12. Treatment repeats every 28 days for up
to 12 courses in the absence of disease progression or unacceptable toxicity.
Cohorts of 3-6 patients receive escalating doses of bortezomib and tipifarnib until the
maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at
which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity.
After completion of study treatment, patients are followed for at least 30 days.
Primary Purpose: Treatment
Maximum tolerated dose of bortezomib in combination with azacytidine
William G. Blum, MD
Ohio State University Comprehensive Cancer Center
|Arthur G. James Cancer Hospital and Richard J. Solove Research Institute at Ohio State University Comprehensive Cancer Center||Columbus, Ohio 43210-1240|