Vorinostat and Azacitidine in Treating Patients With Myelodysplastic Syndromes or Acute Myeloid Leukemia

PRIMARY OBJECTIVES:

I. To evaluate the safety and toxicity of vorinostat in combination with azacitidine in
patients with myelodysplastic syndromes (MDS) and some select patients with acute myeloid
leukemia (AML) (step 1).

II. To identify doses of both vorinostat and azacitidine for safe combination of the 2 agents
that can be administered in repetitive cycles over time for use in phase II studies.

III. To determine the response rate of patients treated with the combination of
suberoylanilide hydroxamic acid (SAHA) (vorinostat) and azacitidine at the doses established
as safe and effective in Step 1 in an expanded cohort of patients with MDS.

IV. To obtain preliminary data on the effects of treatment with the combination of vorinostat
and Aza C (azacitidine) in patients with MDS on a series of biologic surrogate markers
including: deoxyribonucleic acid (DNA) methylation of specific genes (e.g. p15); histone
acetylation; hematopoietic progenitor growth and differentiation; the fate of the MDS clone
and changes in gene expression by array profiling.

SECONDARY OBJECTIVES:

I. Determine effect of treatment with the combination on time to response, time to leukemic
transformation and frequency of transformation to leukemia in patients with MDS during the
phase II segment of the study.

OUTLINE: This is a phase I, dose-escalation study followed by a phase II study.

Patients receive azacitidine subcutaneously (SC) once daily (QD) on days 1-7 and vorinostat
orally (PO) 2-3 times daily on days 3-5, 3-9, or 3-16. Treatment repeats every 28 days for at
least 4 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed monthly for 6 months and then
every 2 months thereafter.

Inclusion Criteria:

- Eligibility Criteria for the phase I portion (step 1); patients must have a diagnosis
of either MDS according to French-American-British (FAB) and International Prognostic
Scoring System (IPSS) criteria, or a diagnosis of AML according to FAB or World Health
Organization (WHO) criteria

- MDS: All patients must have an established diagnosis of myelodysplastic syndrome
confirmed by peripheral blood and bone marrow maturational abnormalities in the
erythroid, megakaryocytic and granulocytic series, defined according to the
French -American-British (F.A.B.) classification

- Refractory anemia (RA), defined as having anemia with =< 1% blasts in the
peripheral blood and dyserythropoiesis; neutropenia and thrombocytopenia may
also be present but are less common; the bone marrow is usually
normocellular or hypercellular with < 5% blast cells

- Refractory anemia with ring sideroblasts (RARS), defined as refractory
anemia above, but also including the presence of ringed sideroblasts
comprising >= 15% of all nucleated cells in the bone marrow

- Refractory anemia with excess blasts (RAEB), defined as having 5-20%
myeloblasts in the bone marrow and less than 5% blasts in the peripheral
blood, together with abnormalities in erythroid megakaryocytic and
granulocytic maturation consistent with myelodysplasia

- Refractory anemia with excess blasts in transformation (RAEB-T), defined as
21-29% myeloblasts in the marrow, or more than 5% blasts in the peripheral
blood, or Auer rods in granulocytic precursors in the marrow or blood (with
< 30% myeloblasts in the marrow)

- Chronic myelomonocytic leukemia (CMMoL) defined as an absolute monocytosis
(> 1 x 10^9/liter) with < 5% blasts in the peripheral blood and < 20% blasts
in the bone marrow; additional criteria include a white blood cell (WBC) =<
13 x 10^9/L

- For patients with refractory anemia or refractory anemia with ring
sideroblasts and IPSS =< 0.5, must also meet at least one of the following
criteria to be eligible:

- Symptomatic anemia requiring packed red blood cell (PRBC) transfusions
for at least 3 months prior to study entry (document), or

- Thrombocytopenia with platelet counts =< 50,000/ml or significant
clinical hemorrhage (e.g., gastrointestinal [GI], gastric ulcer [GU] or
gynecologic [GYN] hemorrhage requiring platelet transfusion; petechiae
alone do not constitute sufficient hemorrhage)

- Neutropenia with absolute neutrophil count < 1000/ul with an infection
requiring treatment with antibiotics

- Patients with MDS classified according to IPSS criteria with intermediate
-1, intermediate -2 or high risk disease are eligible

- Patients with low risk MDS (IPSS Score < 0.5) must additionally meet
criteria as outlined for patients with refractory anemia or refractory
anemia with ring sideroblasts above

- AML - phase 1 only; patients with AML are not eligible for phase II; patients with AML
defined according to FAB or WHO criteria will be eligible for the phase I portion of
this study (phase 1 only); additional selection criteria:

- De novo AML or AML evolving from MDS associated with intermediate or poor risk
cytogenetics in patients who decline standard chemotherapy or who have failed or
relapsed following one prior regimen

- Additionally, patient's disease must be stable i.e. WBC =< 25 x 10^9/L who have
exhibited stable WBC not requiring intervention for WBC control with hydroxyurea,
chemotherapy or leukophoresis for > 4 weeks

- No corticosteroids, interferon or retinoids within one month prior to study

- No treatment with granulocyte colony-stimulating factor (G-CSF),
granulocyte-macrophage colony-stimulating factor (GM-CSF), or other hematopoietic
growth factors, e.g. erythropoietin within one month prior to study

- No prior treatment with azacitidine, decitabine or vorinostat

- Patients should not have taken valproic acid, or any other histone deacetylase
inhibitor, for at least 2 weeks prior to enrollment

- Patients may not have been treated with an investigational agent in the 28 days prior
to study entry and must have recovered from all side effects

- Patients previously treated for cancer other than leukemia with chemotherapy or
radiation therapy may be eligible; they may not have received radiation or
chemotherapy within the past 12 months and must have been free of any evidence of the
malignancy during the past 3 years; patients with a prior history of leukemia who
relapse with MDS are ineligible

- Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)

- Life expectancy of greater than 2 months

- Total bilirubin =< 1.5 x upper limit of normal (ULN); unless the patient has active
hemolysis, or the elevation is secondary to ineffective erythropoiesis

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
=< 2.5 X institutional ULN

- Creatinine within normal institutional limits OR creatinine clearance >= 60
mL/min/1.73 m^2 for patients with creatinine levels above institutional normal

- Treatment must begin within 2 to 4 weeks of completing prestudy tests

- Women of child-bearing potential and men must agree to use adequate contraception
(hormonal or barrier method of birth control; abstinence) prior to study entry and for
the duration of study participation; should a woman become pregnant or suspect she is
pregnant while participating in this study, she should inform her treating physician
immediately

- Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

- Patients who have had chemotherapy or radiotherapy within 12 months prior to entering
the study or those with another malignancy who have had evidence of the malignancy
during the 3 years prior to study entry

- Patients may not be receiving any other investigational agents

- Patients may not have central nervous system (CNS) involvement with MDS or AML

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to vorinostat or other agents used in study

- Pregnant women are excluded from this study; breastfeeding should be discontinued if
the mother is treated with vorinostat

- Any other serious medical or psychiatric illness which would limit survival to < 3
months or prevent the granting of informed consent

- Uncontrolled or severe congestive heart failure; (does not include patients with high
output congestive heart failure [CHF] states secondary to anemia which can be
controlled)

- >= 30% myeloblasts in the bone marrow or M6 leukemia as defined by FAB criteria (phase
II component of the study)

- Prior treatment with G-CSF, GM-CSF, or other hematopoietic growth factors,
erythropoietin within one month prior to study; no interferon or retinoids within one
month prior to study

- Known positive serology for human immunodeficiency virus (HIV); appropriate studies
will be undertaken in patients receiving combination anti-retroviral therapy when
indicated

- Active systemic bacterial, fungal of viral infection; infection should be fully
treated and the patient afebrile for 7 days before study entry

- Prior history of leukemia (step 2 phase II component of the study only)

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, clinically
significant cardiac arrhythmia, or psychiatric illness/social situations that would
limit compliance with study requirements

- Patients with advanced hepatic tumors are excluded