Belinostat and Azacitidine in Treating Patients With Advanced Hematologic Cancers or Other Diseases

PRIMARY OBJECTIVES:

I. Determine the maximum tolerated dose of PXD101 (belinostat) when given in combination
with azacitidine (when azacitidine is utilized at a dose range where its effects on cellular
differentiation are known to be predominant) in patients with advanced hematologic cancers
or other diseases.

SECONDARY OBJECTIVES:

I. Identify any additive or synergistic effects of this regimen on pharmacodynamic
parameters, including apoptosis and re-expression of specific target genes.

II. Assess any evidence of clinical activity (complete remission, partial remission,
hematologic improvement, stable disease) of this regimen in these patients.

OUTLINE: This is a dose-escalation study of belinostat followed by a randomized study.

Patients receive azacitidine subcutaneously (SC) and belinostat intravenously (IV) over 30
minutes on days 1-5. Courses repeat every 28 days in the absence of disease progression or
unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of belinostat until
the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding
that at which 2 of 6 patients experience dose-limiting toxicity. After the MTD is
determined, additional patients with myelodysplastic syndromes (MDS) or acute myeloid
leukemia (with trilineage dysplasia or arising from MDS) are randomized to 1 of 2 treatment
arms.

Arm I: Patients receive azacitidine SC on days 1-5.

Arm II: Patients receive azacitidine as in arm I and belinostat at the MTD IV over 30
minutes on days 1-5.

In both arms, courses repeat every 28 days in the absence of disease progression or
unacceptable toxicity. After receiving one course, patients randomized to arm I may
crossover to receive treatment on arm II.

For patients enrolled in the randomized portion of the study, bone marrow aspirates are
obtained at baseline, and after course 1 for correlative studies. Samples are examined by
gene expression analysis of p15 and p21, DNA methylation of p15INK4B, and apoptosis by
RT-PCR and flow cytometry. Pharmacodynamic assays are also performed.

After completion of study treatment, patients are followed periodically for up to 2 years.

Inclusion Criteria:

- Histologically confirmed diagnosis of 1 of the following:

- Relapsed or refractory acute myeloid leukemia (AML)

- Relapsed or refractory acute promyelocytic leukemia (must have failed both
tretinoin and arsenic trioxide)

- Relapsed or refractory acute lymphoblastic leukemia

- Secondary AML, including AML arising from antecedent hematologic diseases, such
as myelodysplastic syndromes (MDS) or myeloproliferative disorders, OR
therapy-related AML

- Chronic myelogenous leukemia in accelerated or blast phase

- Advanced phases of Philadelphia chromosome-negative (Ph-) chronic
myeloproliferative disorders, as defined by ≥ 1 of the following:

- Presence of anemia (hemoglobin < 10 g/dL and/or red blood cell transfusion
dependent)

- Presence of palpable splenomegaly

- MDS, including chronic myelomonocytic leukemia

- Must have intermediate or high-risk International Prognostic Scoring System
(IPSS) scores (≥ 0.5)

- Low-risk IPSS scores allowed provided ≥ 1 of the following criteria are
met:

- Hemoglobin < 10 g/dL and/or red blood cell transfusion dependent

- Platelet count < 50,000/mm³

- Absolute neutrophil count < 1,000/mm³

- Refractory disease OR no standard therapy exists

- Evidence of AML associated with dysplasia on bone marrow histology for elderly
patients (i.e., > 60 years old) who are previously untreated and not candidates for
or unwilling to undergoing induction therapy

- No known active CNS involvement with disease

- CALGB performance status (PS) 0-2 OR Karnofsky PS 60-100%

- Bilirubin ≤ 2.0 mg/dL (unless due to Gilbert's syndrome)

- ALT ≤ 3 times upper limit of normal (unless due to disease)

- Creatinine ≤ 2 mg/dL

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception

- No history of allergic reactions attributed to compounds of similar chemical or
biologic composition to PXD101 or Azacitidine

- No history of allergic reactions to mannitol

- No history of dose-limiting toxicity during prior treatment with Azacitidine

- No concurrent uncontrolled illness including, but not limited to, the following:

- Ongoing or active infection

- Symptomatic congestive heart failure

- Unstable angina pectoris

- Cardiac arrhythmia

- Psychiatric illness or social situation that would preclude compliance with
study requirements

- No marked baseline prolongation of QT/QTc interval (e.g., repeated demonstration of a
QTc interval > 500 msec)

- No long QT syndrome

- No uncontrolled cardiovascular disease, including the following:

- Severe uncontrolled hypertension

- Uncontrolled congestive heart failure related to primary cardiac disease

- Uncontrolled cardiac arrhythmia

- Uncontrolled ischemic or severe valvular heart disease

- Myocardial infarction within the past 6 months

- See Disease Characteristics

- Recovered from prior therapy

- At least 2 weeks since prior chemotherapy (6 weeks for mitomycin C or nitrosoureas)

- At least 2 weeks since prior radiotherapy

- At least 4 weeks since prior investigational agents

- At least 24 hours since prior hydroxyurea

- At least 2 weeks since prior valproic acid

- No concurrent combination antiretroviral therapy for HIV-positive patients

- No other concurrent investigational agents

- No concurrent medication that may cause torsade de pointes

- No other concurrent anticancer therapy, including chemotherapy, radiotherapy, or
biological agents