AML-02: Omacetaxine With Standard-of-Care Induction With Cytarabine & Idarubicin in Newly-Diagnosed AML Patients

This is a dose escalation study to evaluate Omacetaxine when given in combination with a
standard induction regimen of "7+3" (cytarabine for Days 1-7 and Idarubicin for Days 1-3) in
patients with newly diagnosed acute myelogenous leukemia (AML). Omacetaxine will be given
subcutaneously Q12 hours on Days 1-7. The optimally safe and active dose (OD) will be
determined using the EffTox design. EffTox is a Bayesian adaptive design that seeks to
determine the optimal dose for further study in Phase II by considering a trade-off between
efficacy and toxicity. The EffTox design begins by treating a cohort of three patients at
dose level 1. These patients' efficacy and toxicity outcomes are used to update the posterior
distributions for the probability of efficacy and toxicity and identify acceptable dose
levels. The study terminates if no dose levels are acceptable. Otherwise, the acceptable
doses are ranked using the Euclidean distance from (1.0, 0.0) and the next cohort is treated
at the dose with the minimum distance under the restriction that we may only escalate or
deescalate by one dose level at a time (e.g., the second cohort can only escalate to dose
level 2 or deescalate to dose level -1). The second cohort is treated at the dose with the
minimum distance and posterior distributions, and the list of acceptable doses and distances
are updated as before. This process continues until at least 20 subjects are enrolled in the
study. The dose with the minimum distance at study completion is considered the optimal dose
for further investigation. If none of the dose levels are acceptable at study completion, an
optimal dose level will not be identified and the drug does not warrant further
investigation.

Post induction therapy will consist of standard cytarabine consolidation chemotherapy or
allogeneic stem cell transplantation based on pretreatment risk assessment.

Inclusion Criteria:

1. Newly diagnosed, untreated patients with AML according to the WHO classification for
AML. Prior short-term therapy (≤7 days) with hydroxyurea, steroids, biological or
targeted therapy (e.g. FLT3 inhibitors, other kinase inhibitors, azacitidine, ATRA),
or hematopoietic growth factors is allowed. A single or two-day dose of cytarabine (up
to 3 g/m^2) for emergency use is also allowed as prior therapy.

2. Patients age 18 to 70 years old who meet diagnostic criteria for AML according to the
WHO classification for AML.

3. Previously untreated AML (≥20% blasts). Note that prior short-term therapy (≤7 days)
with hydroxyurea, steroids, biological or targeted therapy (e.g. FLT3 inhibitors,
other kinase inhibitors, azacitidine, ATRA), or hematopoietic growth factors is
allowed. A single or two-day dose of cytarabine (up to 3 g/m2) for emergency use is
also allowed as prior therapy.

4. ECOG performance status of 0-3

5. Adequate organ function, if not suspected to be due to AML, within 14 days of study
registration, defined as:

Total bilirubin ≤ 2.0 x ULN (unless due to hemolysis) AST and ALT ≤ 3 X ULN (unless
believed to be due to tumor involvement) Serum Creatinine ≤ 1.5 x ULN Creatinine
Clearance > 30 ml/min

6. Negative urine or serum pregnancy test in females. Patients of reproductive potential
(males and females) must consent to and practice double-barrier methods of
contraception during treatment and for 12 weeks following the last dose of
Omacetaxine. Adequate contraception is defined as double-barrier protection (i.e.,
condom plus spermicide in combination with a diaphragm, cervical/vault cap, or
intrauterine device). Birth control pills, birth control patches and/or injections of
hormones to prevent pregnancy are not considered an adequate method of preventing
pregnancy, and double-barrier protection is required while on study and for 12 weeks
after last dose. Patients will be instructed to notify the investigator if pregnancy
is discovered either during or within 12 weeks of completing treatment with
Omacetaxine. This also applies to male patients whose partners become pregnant while
the patient is on study or within the 12 week period after the last dose of study
drug.

7. Patients must be willing and able to review, understand, and provide written consent
before starting therapy.

Exclusion Criteria:

1. Acute promyelocytic leukemia.

2. Investigational drug within 4 weeks of study entry.

3. Cardiac insufficiency grade III or IV New York Heart Association (NYHA)

4. Female subjects who are pregnant or breast feeding.

5. Patients who are HIV positive.

6. Active uncontrolled infection or severe systemic infection (enrollment is possible
after control of infection).

7. Concurrent malignancy (other than AML) with an estimated life expectancy less than two
years and requiring active therapy.

8. Psychological, familial, sociological, or geographical condition that would preclude
study compliance and follow-up.

9. Uncontrolled angina, severe uncontrolled ventricular arrhythmias, or
electrocardiographic evidence of acute ischemia or medically relevant active
conduction system abnormalities. Prior to study entry, any ECG abnormality at
screening has to be documented by the investigator as not medically relevant.

10. Pregnant or breastfeeding: Omacetaxine is a Pregnancy Category D medication and has
caused embryo-fetal death in animals. Confirmation that the subject is not pregnant
must be established by a negative urine β-human chorionic gonadotropin (β-hCG)
pregnancy test result obtained during screening. Pregnancy testing is not required for
post-menopausal or surgically sterilized women.

11. Other severe acute or chronic medical or psychiatric condition, or laboratory
abnormality that may increase the risk associated with study participation or
investigational product administration or may interfere with the interpretation of
study results and, in the judgment of the investigator, would make the patient
inappropriate for enrollment in this study.