AR-42 and Decitabine in Treating Patients With Acute Myeloid Leukemia

PRIMARY OBJECTIVES:

I. To determine the biologic effective and tolerable dose (BETD) of AR-42 (histone
deacetylase [HDAC] inhibitor AR-42) in combination with a 10 day schedule of decitabine in
acute myeloid leukemia (AML) in adults (Stratum 1) and children (Stratum 2).

II. To define the specific toxicities and the dose limiting toxicity (DLT) of AR-42 in
combination with a 10 day schedule of decitabine in adults and children.

SECONDARY OBJECTIVES:

I. To describe biologic activity of the combination of AR-42 and decitabine (changes in micro
ribonucleic acid [RNA] [miR]-29b expression; specificity protein 1 [Sp1], deoxyribonucleic
acid [DNA] (cytosine-5-)-methyltransferase [DNMT]1, 3A and 3B, KIT and FMS-like tyrosine
kinase 3 [FLT3] RNA and protein levels).

II. To provide preliminary data for clinical response with the combination of AR-42 and
decitabine in adults and in children.

III. To provide preliminary data on correlation of biologic endpoints and clinical response
(particularly miR-29b expression).

OUTLINE: This is a dose-escalation study of HDAC inhibitor AR-42.

INDUCTION THERAPY: Patients receive HDAC inhibitor AR-42 orally (PO) daily on days 1, 3, and
5 or 1, 3, 4, 5 and decitabine intravenously (IV) over 1 hour on days 6-15. Treatment repeats
every 28 days for up to 3 courses in the absence of disease progression or unacceptable
toxicity.

MAINTENANCE THERAPY: Patients achieving complete remission (CR) or morphologic CR with
incomplete blood count recovery (CRi) receive HDAC inhibitor AR-42 as in Induction Therapy
and decitabine IV over 1 hour on days 6-10. Courses repeat every 28 days in the absence of
disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up periodically.

Inclusion Criteria:

- Adult patients (stratum 1) must be age >= 18 with relapsed or refractory acute myeloid
leukemia (AML) or age >= 60 with previously untreated AML who are not candidates for
or refuse standard/conventional induction chemotherapy (e.g. the 7+3 combination of
cytarabine and an anthracycline); pediatric patients, age 3 to < 18 years (stratum 2)
will be eligible with AML in second relapse or with refractory disease

- Patients with secondary AML or therapy related disease (t-AML) are eligible

- Patients who received decitabine or 5-azacitidine as prior treatment for
myelodysplastic syndrome (MDS) (or AML) remain eligible for the dose escalation phase
of the study; however, neither of these agents is permitted within 3 months of study
entry; patients who have received prior decitabine or 5- azacitidine will be excluded
from the expansion phase of the trial

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

- Performance status: Adults (>= 18 years) must be Eastern Cooperative Oncology Group
(ECOG) performance status =< 2; pediatric patients (< 18 years) must be at least
Lansky > 50%

- 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 (adults > 18 years); < 1.3 x upper limit normal for age
(pediatric patients < 18 years)

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

- The effects of decitabine and AR-42 on the developing human fetus at the recommended
therapeutic dose are unknown; for this reason, both men and women must agree to use
adequate contraception (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 the study, she should inform her treating physician immediately

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

- 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; hydroxyurea may be
administered for control of leukocytosis both pre-treatment and during cycle 1 only

- Patients receiving any other investigational agents or patients that have received
other investigational agents within 28 days of enrollment

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

- Patients with a history of allergic reactions attributed to compounds of similar
chemical or biologic composition to decitabine or AR-42 that cannot be managed with
oral antihistamines, antipyretics (ie. acetaminophen) or low dose corticosteroids (<
10 mg oral prednisone or equivalent corticosteroid)

- 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; as infection is a common feature of AML, patients with active infection
are permitted to enroll provided that the infection is under control; myocardial
infarction within 6 months prior to enrollment or has New York Heart Association
(NYHA) class III or IV heart failure, uncontrolled angina, uncontrolled hypertension,
severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute
ischemia or active conduction system abnormalities

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

- Patients with a known confirmed diagnosis of human immunodeficiency virus (HIV)
infection (due to concern for increased toxicity with the regimen in combination with
highly active antiretroviral therapy [HAART])

- Patients with a known diagnosis of chronic hepatitis B infection (ie. persistence of
hepatitis B surface antigen in the blood for 6 months or longer) or a diagnosis of
hepatitis C (ie. the presence of anti-hepatitis C (hepatitis C virus [HCV]) antibodies
in the peripheral blood) are excluded; patients with a recent diagnosis (< 6 months)
of active viral hepatitis B or C are excluded

- Patients who have advanced malignant solid tumors at the time of consideration for
enrollment on this trial are excluded; patients who have a history of an advanced
malignant solid tumor, but have no evidence of disease at the time of consideration
for enrollment, are eligible

- Patients with a known impairment of gastrointestinal (GI) function due to a GI disease
such as inflammatory bowel disease (Crohn's disease, ulcerative colitis) or celiac
disease, that may significantly alter the absorption of AR-42 are excluded

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

- Diagnosis of prolonged QT syndrome

- Patients with a mean corrected QT interval (QTc) > 450 msec in males and > 470 msec in
females

- Inability to swallow capsules