Azacytidine and Bortezomib 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.

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