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

The recruitment status of this study is unknown. The completion date has passed and the status has not been verified in more than two years.
Verified June 2009 by National Cancer Institute (NCI).
Recruitment status was:  Recruiting
National Cancer Institute (NCI)
Information provided by:
National Cancer Institute (NCI) Identifier:
First received: February 27, 2008
Last updated: April 9, 2010
Last verified: June 2009

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 Intervention Phase
Leukemia Myelodysplastic Syndromes Myelodysplastic/Myeloproliferative Neoplasms Drug: azacitidine Drug: bortezomib Phase 1

Study Type: Interventional
Study Design: Primary Purpose: Treatment
Official Title: Phase I Study of Vidaza and Velcade (Bortezomib) in Acute Myeloid Leukemia

Resource links provided by NLM:

Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • Maximum tolerated dose of bortezomib in combination with azacytidine
  • Overall response rate

Secondary Outcome Measures:
  • 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

Estimated Enrollment: 18
Study Start Date: April 2008
Estimated Primary Completion Date: March 2011 (Final data collection date for primary outcome measure)
Detailed Description:



  • 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.


Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No


  • Diagnosis of acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS)

    • High risk (by IPSS scoring)
    • Relapsed or refractory disease
    • Secondary AML or therapy related disease (t-AML) allowed
  • No active central nervous system disease or granulocytic sarcoma as sole site of disease
  • No advanced malignant solid tumors


Inclusion criteria:

  • 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 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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its identifier: NCT00624936

United States, Ohio
Arthur G. James Cancer Hospital and Richard J. Solove Research Institute at Ohio State University Comprehensive Cancer Center Recruiting
Columbus, Ohio, United States, 43210-1240
Contact: William G. Blum, MD    866-627-7616      
Sponsors and Collaborators
Ohio State University Comprehensive Cancer Center
National Cancer Institute (NCI)
Principal Investigator: William G. Blum, MD Ohio State University Comprehensive Cancer Center
Principal Investigator: Guido Marcucci, MD Ohio State University Comprehensive Cancer Center
  More Information Identifier: NCT00624936     History of Changes
Other Study ID Numbers: CDR0000588051
OSU IRB-2008C0004
Study First Received: February 27, 2008
Last Updated: April 9, 2010

Keywords provided by National Cancer Institute (NCI):
adult acute myeloid leukemia with 11q23 (MLL) abnormalities
adult acute myeloid leukemia with inv(16)(p13;q22)
adult acute myeloid leukemia with t(15;17)(q22;q12)
adult acute myeloid leukemia with t(16;16)(p13;q22)
adult acute myeloid leukemia with t(8;21)(q22;q22)
recurrent adult acute myeloid leukemia
myelodysplastic/myeloproliferative neoplasm, unclassifiable
myelodysplastic syndromes
secondary acute myeloid leukemia

Additional relevant MeSH terms:
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Myelodysplastic Syndromes
Myeloproliferative Disorders
Myelodysplastic-Myeloproliferative Diseases
Pathologic Processes
Neoplasms by Histologic Type
Bone Marrow Diseases
Hematologic Diseases
Precancerous Conditions
Antineoplastic Agents
Antimetabolites, Antineoplastic
Molecular Mechanisms of Pharmacological Action
Enzyme Inhibitors processed this record on August 18, 2017