Tosedostat in Combination With Cytarabine or Decitabine in Treating Patients With Newly Diagnosed Acute Myeloid Leukemia or High-Risk Myelodysplastic Syndrome

PRIMARY OBJECTIVES:

I. To determine the 4 month survival and complete remission (CR) rates of tosedostat in
combination with either cytarabine or decitabine in untreated acute myeloid leukemia (AML)
or high-risk myelodysplastic syndrome (MDS).

SECONDARY OBJECTIVES:

I. To assess safety and tolerability of tosedostat in combination with either cytarabine or
decitabine.

II. To determine the treatment related mortality defined as death within the first 30 days
of beginning treatment.

III. To estimate rates of disease-free survival (DFS) and the 1 year overall survival (OS).

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive tosedostat orally (PO) once daily (QD) on days 1-21 and cytarabine
intravenously (IV) on days 1-5.

ARM II: Patients receive tosedostat PO QD on days 1-21 and decitabine IV on days 1-5.

In both arms, treatment repeats every 35 days for up to 3 courses in the absence of disease
progression or unacceptable toxicity. Patients achieving CR or partial CR (pCR) may receive
2 additional courses of treatment.

After completion of study treatment, patients are followed up every 3 months for 2 years and
then annually for 3 years.

Inclusion Criteria:

- Capable of understanding the investigational nature, potential risks and benefits of
the study, and able to provide valid informed consent

- All adults >= 60 years of age with untreated AML or high-risk MDS (10-19% marrow
blasts) including those with prior myelodysplasia (MDS)/AML, therapy-related AML, AML
with trilineage dysplasia (AML-TLD), and AML with adverse cytogenetics; patients may
be enrolled if they received prior treatment with hydroxyurea to control blood counts
or demethylating agents specifically for the purpose of treating MDS

- Adults age 18 to 59 with untreated AML or high-risk MDS and a transplant-related
mortality (TRM) score of >= 9.2; previous data suggests these people would have a 25%
mortality with standard therapy, making this treatment a reasonable alternative

- Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 - 2

- Serum creatinine =< 2.0 mg/dL; if serum creatinine > 2.0 mg/dL, then the estimated
glomerular filtration rate (GFR) must be > 50 mL/min/1.73 m^2 as calculated by the
Modification of Diet in Renal Disease equation

- Serum bilirubin =< 1.5 × upper limit of normal (ULN) (in the absence of Gilbert's
syndrome)

- Aspartate transaminase (AST)/alanine transaminase (ALT) =< 2.5 × ULN

- Alkaline phosphatase =< 2.5 × ULN

- Male subjects, even if surgically sterilized (i.e., status postvasectomy) must agree
to 1 of the following: practice effective barrier contraception during the entire
study treatment period and through a minimum of 30 days after the last dose of study
drug, or completely abstain from heterosexual intercourse

- Female subject is either postmenopausal for at least 1 year before the screening
visit, is surgically sterilized or if they are of childbearing potential, agree to
practice 2 effective methods of contraception from the time of signing the informed
consent form through 30 days after the last dose of study drug, or agree to
completely abstain from heterosexual intercourse

Exclusion Criteria:

- Favorable AML features defined as the following:

- t(8;21)(q22;q22); RUNX1-RUNX1T1

- inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB-MYH11

- Mutated nucleophosmin (NPM)1 without fms-like tyrosine kinase receptor-3
(FLT3)-internal tandem duplication (ITD) (normal karyotype)

- Mutated CCAAT/Enhancer Binding Protein Alpha (CEBPA) (normal karyotype)

- Current concomitant chemotherapy, radiation therapy, or immunotherapy other than as
specified in the protocol

- Active uncontrolled infection

- Known infection with human immunodeficiency virus (HIV)

- Medical condition, serious concurrent illness, or other extenuating circumstance
that, in the judgment of the Principal Investigator, could jeopardize patient safety
or interfere with the objectives of the study

- Uncontrolled angina or myocardial infarction within 6 months

- Current or history of congestive heart failure New York Heart Association (NYHA)
class 3 or 4, unless a screening echocardiogram (ECHO) or multiple gate acquisition
scan (MUGA) performed within 1 month prior to study screening results in a left
ventricular ejection fraction (LVEF) that is >= 45% (or institutional lower limit of
normal value)

- Diagnosed or treated for another malignancy within 1 year of enrollment, with the
exception of complete resection of basal cell carcinoma or squamous cell carcinoma of
the skin, an in situ malignancy, or low-risk prostate cancer after curative therapy