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

Sponsor

Ohio State University Comprehensive Cancer Center (Other)

Overall Status

Completed

CT.gov ID

NCT00624936

Collaborator

Millennium Pharmaceuticals, Inc. (Industry), Celgene Corporation (Industry)

Enrollment

Location

Arm

Actual Duration (Months)

0.3

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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

Detailed Description

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

23 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Phase I Study of Vidaza and Velcade (Bortezomib) in Acute Myeloid Leukemia

Actual Study Start Date :

Apr 1, 2008

Actual Primary Completion Date :

Dec 1, 2009

Actual Study Completion Date :

Jun 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
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	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 Names: Bortezomib

Arm

Intervention/Treatment

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

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 Names:

Bortezomib

Outcome Measures

Primary Outcome Measures

Maximum tolerated dose of bortezomib in combination with azacytidine [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 [Up to 1 year]
Determine the overall response rate (ORR)

Secondary Outcome Measures

Rate of complete remission [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 [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 [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 [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 [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.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Ohio State University Medical Center	Columbus	Ohio	United States	43210

Sponsors and Collaborators

Ohio State University Comprehensive Cancer Center
Millennium Pharmaceuticals, Inc.
Celgene Corporation

Investigators

Principal Investigator: William G. Blum, MD, Ohio State University
Principal Investigator: Guido Marcucci, MD, Ohio State University Comprehensive Cancer Center