Azacytidine and Bortezomib in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia or Myelodysplastic Syndromes
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|ClinicalTrials.gov Identifier: NCT00624936|
Recruitment Status : Completed
First Posted : February 28, 2008
Last Update Posted : August 22, 2017
RATIONALE: Drugs used in chemotherapy, such as azacytidine work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Bortezomib may stop the growth of cancer cells by blocking blood flow to the cancer and by blocking some of the enzymes needed for cell growth. Giving azacytidine together with bortezomib may kill more cancer cells.
PURPOSE: This phase I trial is studying the side effects and best dose of bortezomib when giving together with azacytidine in treating patients with relapsed or refractory acute myeloid leukemia or myelodysplastic syndromes.
|Condition or disease||Intervention/treatment||Phase|
|Leukemia Myelodysplastic Syndromes Myelodysplastic/Myeloproliferative Neoplasms||Drug: Vidaza Drug: Velcade||Phase 1|
- 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 agent.
- 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 endpoints.
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.
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||23 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||Phase I Study of Vidaza and Velcade (Bortezomib) in Acute Myeloid Leukemia|
|Actual Study Start Date :||April 2008|
|Primary Completion Date :||December 2009|
|Study Completion Date :||June 2014|
Experimental: Vidaza and Velcade
Vidaza 75mg/m2 IV over 30 min daily on days 1-7 This dose is the same for all dose levels. Velcade will be given immediately after Vidaza is completed at one of the following dose levels: 1, 2, 3, 4
Vidaza 75mg/m2 IV over 30min daily on days 1-7. This dose is the same for all dose levels.
Other Names:Drug: Velcade
Dose level 1 Velcade 0.7mg/m2 IVP on days 2 and 5 Dose level 2 Velcade 0.7mg/m2 IVP on days 2, 5, 9, 12 Dose level 3 Velcade 1.0 mg/m2 IVP on days 2, 5, 9, 12 Dose level 4 Velcade 1.3 mg/m2 IVP on days 2, 5, 9, 12
Other Name: Bortezomib
- Maximum tolerated dose of bortezomib in combination with azacytidine [ Time Frame: Up to 1 year ]Determine the maximum tolerated dose (MTD) of Velcade (bortezomib, PS-341) in combination with Vidaza in patients with relapsed/refractory acute myeloid leukemia (AML) and Myelodysplastic Syndrome (MDS)
- Overall response rate [ Time Frame: Up to 1 year ]Determine the overall response rate (ORR)
- Rate of complete remission [ Time Frame: Up to 1 year ]Determine the rate of complete remission (CR) of Vidaza plus Velcade in relapsed/refractory AML and MDS
- Biological activity of azacytidine and bortezomib as demethylating agents [ Time Frame: Up to 1 year ]Correlate the biological activity of Vidaza as demethylating agent (changes in target gene methylation and gene expression, DNMT1 protein expression, global methylation) with clinical endpoints and plasma pharmacokinetics of Vidaza
- Correlation of intracellular concentration of azacytidine-triphosphate with global DNA methylation and other biological endpoints as well as clinical response [ Time Frame: Up to 1 year ]Characterize the biological activity of Velcade as a potential demethylating
- Biologic role of microRNAs in determining clinical response to study drugs [ Time Frame: Up to 1 year ]Correlate intracellular concentration of Vidaza-triphosphate with global DNA methylation and other biological endpoints as well as clinical response
- Achievement of other pharmacodynamic endpoints [ Time Frame: Up to 1 year ]Explore the biologic role of microRNAs in determining clinical response to the Vidaza plus Velcade combination and achievement of the other pharmacodynamic endpoints.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00624936
|United States, Ohio|
|Ohio State University Medical Center|
|Columbus, Ohio, United States, 43210|
|Principal Investigator:||William G. Blum, MD||Ohio State University|
|Principal Investigator:||Guido Marcucci, MD||Ohio State University Comprehensive Cancer Center|