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