Decitabine, Vorinostat, and Cytarabine in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia or Myelodysplastic Syndrome

PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose (MTD) of the combination of decitabine,
vorinostat, and cytarabine in patients with relapsed/refractory acute myeloid leukemia (AML)
and select subsets of high risk leukemia/myelodysplastic syndromes (MDS).

II. To define the specific toxicities and the dose limiting toxicity (DLT) of the
combination.

SECONDARY OBJECTIVES:

I. To develop a platform for specifically targeting mixed-lineage leukemia partial-tandem
duplication (MLL PTD), for future efficacy studies.

II. To determine the overall response rate (ORR) of this regimen in relapsed/ refractory AML.

III. To examine the role of decitabine and vorinostat in re-expression of mixed-lineage
leukemia wild type (MLL- WT) in patients with MLL PTD via correlative studies specific to
patients with MLL PTD and the preliminary relationship of this to clinical response in
patients with MLL PTD+ AML.

IV. To correlate the biological activity of decitabine as demethylating agent (changes in
target gene methylation and gene expression, deoxyribonucleic acid [DNA]
[cytosine-5-]-methyltransferase 1 [DNMT1] protein expression, global methylation) with
clinical endpoints.

V. To explore the biologic role of microribonucleic acids (RNAs) in determining clinical
response to the combination and achievement of the other pharmacodynamic endpoints.

OUTLINE: This is a dose-escalation study of cytarabine.

INDUCTION THERAPY: Patients receive decitabine intravenously (IV) over 1 hour on days 1-10;
vorinostat orally (PO) on days 5-10; and high-dose cytarabine IV over 2 hours on days 12, 14,
and 16 in the absence of disease progression or unacceptable toxicity. Patients who achieve
complete remission (CR) proceed to maintenance therapy. Patients who achieve CR with
incomplete blood count recovery undergo bone marrow aspiration and biopsy at count recovery
or day 42 before proceeding to maintenance therapy.

MAINTENANCE THERAPY: Patients receive decitabine IV over 1 hour on days 1-5 and vorinostat PO
on days 5-10. Treatment repeats every 28 days for up to 11 courses in the absence of disease
progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 30 days.

Inclusion Criteria:

- Patients with relapsed or refractory acute myeloid leukemia (AML)

- Patients aged between 55-59.9 with previously untreated AML will also be eligible, but
these patients must be screened for AML-core binding factor (CBF)+ AML is NOT eligible
in this subset of previously untreated AML patients

- Patients with relapsed or refractory high risk MDS (defined as International
Prognostic Scoring System [IPSS] score >= 1.5) will also be eligible; IPSS score can
be calculated any time from myelodysplastic syndrome (MDS) diagnosis at
relapse/treatment failure for the purposes of trial eligibility

- Patients with secondary AML or therapy related disease (t-AML) are eligible; patients
who received decitabine or 5-azacytidine as prior treatment for MDS (or AML) are
eligible; patients who previously received high dose cytarabine (>= 1 gm/m^2/dose) are
eligible

- If the patient has co-morbid medical illness, life expectancy attributed to this must
be greater than 6 months

- Eastern Cooperative Oncology Group (ECOG) performance status =< 2

- Total bilirubin < 2.0 mg/dL

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
< 2.5 X institutional upper limit of normal

- Creatinine < 2.0 mg/dL

- New York Heart Association (NYHA) congestive heart failure (CHF) class II or better

- 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; if the patient does not agree, the patient is not
eligible; 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 willingness to sign the written informed consent document

- Patients with known human immunodeficiency virus (HIV) infection without a history of
acquired immune deficiency syndrome (AIDS) and with sufficiently high cluster of
differentiation (CD)4 cells (> 400/mm^3) and low HIV viral loads (< 30,000 copies/ml
plasma) not requiring anti-HIV therapy are eligible

- Patients must have recovered from the toxicity of prior therapy to less than grade 2

Exclusion Criteria:

- Patients who have had chemotherapy or radiotherapy within 2 weeks (6 weeks for
nitrosoureas or mitomycin C) prior to entering the study, or those who have not
recovered from adverse events (to less than grade 2) due to agents administered more
than 4 weeks earlier

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

- Patients receiving any other investigational agents or patients that have received
other investigational agents within 14 days of enrollment

- Patients with active central nervous system disease or with granulocytic sarcoma as
sole site of disease

- Patients with history of medically serious allergic reactions attributed to
decitabine, vorinostat, or cytarabine or compounds of similar chemical or biologic
composition that are not easily managed

- Patients with the following will be excluded: uncontrolled intercurrent illness
including, but not limited to, symptomatic congestive heart failure, unstable angina
pectoris, serious cardiac arrhythmia, or psychiatric illness/social situations that
would limit compliance with study requirements, myocardial infarction within 6 months
prior to enrollment, New York Heart Association (NYHA) class III or IV heart failure,
severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute
ischemia or active conduction system abnormalities; patients with medical
comorbidities that will preclude safety evaluation of the combination should not be
enrolled

- Patients with serious medical or psychiatric illness likely to interfere with
participation in this clinical study

- Pregnant women or women who are breastfeeding; breastfeeding should be discontinued;
confirmation that the subject is not pregnant must be established by a negative serum
beta-human chorionic gonadotropin (beta-hCG) pregnancy test result obtained during
screening; pregnancy testing is not required for post-menopausal or surgically
sterilized women

- Patients with advanced malignant solid tumors are excluded; patients with active
additional hematologic malignancies are excluded

- Patients with a history of neurologic toxicity with cytarabine or vorinostat are
excluded

- Patients with active infection are permitted to enroll provided that the infection is
under control; patients with uncontrolled infection shall not be enrolled until
infection is treated and brought under control

- Patients who are unable to swallow pills are excluded

- Patients requiring warfarin are excluded