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Azacytidine and Bortezomib in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia or Myelodysplastic Syndromes

This study has been completed.
Sponsor:
ClinicalTrials.gov Identifier:
NCT00624936
First Posted: February 28, 2008
Last Update Posted: August 22, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Collaborators:
Millennium Pharmaceuticals, Inc.
Celgene Corporation
Information provided by (Responsible Party):
Ohio State University Comprehensive Cancer Center
February 27, 2008
February 28, 2008
August 22, 2017
April 2008
December 2009   (Final data collection date for primary outcome measure)
  • 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)
  • Maximum tolerated dose of bortezomib in combination with azacytidine
  • Overall response rate
Complete list of historical versions of study NCT00624936 on ClinicalTrials.gov Archive Site
  • 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.
  • Rate of complete remission
  • Biological activity of azacytidine and bortezomib as demethylating agents
  • Correlation of intracellular concentration of azacytidine-triphosphate with global DNA methylation and other biological endpoints as well as clinical response
  • Biologic role of microRNAs in determining clinical response to study drugs
  • Achievement of other pharmacodynamic endpoints
Not Provided
Not Provided
 
Azacytidine and Bortezomib in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia or Myelodysplastic Syndromes
Phase I Study of Vidaza and Velcade (Bortezomib) in Acute Myeloid Leukemia

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.

OBJECTIVES:

Primary

  • 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.

Secondary

  • 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.

Interventional
Phase 1
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
  • Leukemia
  • Myelodysplastic Syndromes
  • Myelodysplastic/Myeloproliferative Neoplasms
  • Drug: Vidaza
    Vidaza 75mg/m2 IV over 30min daily on days 1-7. This dose is the same for all dose levels.
    Other Names:
    • Azacitidina
    • Azacitidinum
    • Azacytidine
    • Mylosar
  • 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
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
Interventions:
  • Drug: Vidaza
  • Drug: Velcade
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
23
June 2014
December 2009   (Final data collection date for primary outcome measure)

Inclusion criteria:

  • Patients must be >18 with relapsed or refractory acute myeloid leukemia (AML) and high risk (by IPSS scoring) Myelodysplastic Syndromes (MDS)
  • Patients with secondary AML or therapy related disease (t-AML) are eligible If decitabine or Vidaza was a prior treatment for MDS or AML patient is eligible.Prior Velcade is also permitted.
  • ECOG performance status 0-2
  • Life expectancy > 6 months for patients with a co-morbid medical illness
  • Total bilirubin < 2.0mg/dL
  • AST/ALT < 2.5 times upper limit of normal (ULN)
  • Creatinine < 2.0 mg/dL
  • Not pregnant or nursing
  • Negative pregnancy test
  • Fertile patients must use effective contraception prior to and during study treatment
  • Ability to understand and willingness to sign the written informed consent document
  • Active infection is allowed provided it is under control

Exclusion criteria:

  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to azacytidine or bortezomib that are not easily managed
  • Hypersensitivity to bortezomib, boron, or mannitol
  • Uncontrolled intercurrent illness including, but not limited to:

    • Symptomatic congestive heart failure
    • Unstable angina pectoris
    • Serious cardiac arrhythmia
    • Psychiatric illness/social situations that would limit compliance with study
  • Myocardial infarction within 6 months prior to enrollment
  • New York Heart Association (NYHA) Class III or IV congestive heart failure
  • Uncontrolled angina
  • Severe uncontrolled ventricular arrhythmia
  • Electrocardiographic evidence of acute ischemia
  • Active conduction system abnormalities
  • ECG abnormality that is medically relevant
  • Psychiatric conditions that prevent compliance with protocol or consent.
  • Pre-existing neuropathy grade 2 or higher or other serious neurologic toxicity that would significantly increase risk of complications from bevacizumab therapy
  • Serious medical or psychiatric illness likely to interfere with participation in this clinical study
  • Diagnosis or treatment for another malignancy within 3 years of enrollment, with the exception of any of the following:

    • Complete resected basal cell carcinoma
    • Squamous cell carcinoma of the skin
    • Any in situ malignancy
    • Low-risk prostate cancer after curative therapy

PRIOR CONCURRENT THERAPY:

  • Prior decitabine or azacytidine for MDS or AML is allowed
  • Prior bortezomib allowed
  • More than 2 weeks since prior chemotherapy or radiotherapy (6 weeks for nitrosoureas or mitomycin C)
  • More than 14 days since prior and no concurrent investigational agents
  • No concurrent combination antiretroviral therapy for HIV-positive patients
Sexes Eligible for Study: All
18 Years and older   (Adult, Senior)
No
Contact information is only displayed when the study is recruiting subjects
United States
 
 
NCT00624936
OSU-07095
NCI-2011-03146 ( Registry Identifier: Clinical Trial Reporting Program (CTRP) )
Yes
Not Provided
Not Provided
Ohio State University Comprehensive Cancer Center
Ohio State University Comprehensive Cancer Center
  • Millennium Pharmaceuticals, Inc.
  • Celgene Corporation
Principal Investigator: William G. Blum, MD Ohio State University
Principal Investigator: Guido Marcucci, MD Ohio State University Comprehensive Cancer Center
Ohio State University Comprehensive Cancer Center
August 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP