Study of Dasatinib and All-Trans Retinoic Acid for Relapsed/Refractory and/or Elderly Patients With Acute Myelogenous Leukemia (AML) or Myelodysplastic Syndrome

Primary Objective:

1. To determine the safety and tolerability of the combination of dasatinib and ATRA in
relapsed or elderly, non-induction candidate acute myelogenous leukemia (AML) or MDS
patients and to identify the maximally tolerated dose (MTD), dose-limiting toxicities (DLT).

Secondary Objectives:

1. To determine the pharmacokinetic (PK) profiles of dasatinib and ATRA when administered
as combination therapy for patients with AML or MDS

2. To determine if the combination therapy of dasatinib and ATRA promotes differentiation
of AML or MDS .

Inclusion

- Informed consent

- Performance Status (ECOG) less than or equal to 3

- Subjects ages 18 or older

- Confirmed diagnosis of non-APL AML (WHO criteria) or high-risk MDS (IPSS criteria
INT-2 or High)

- For subjects Age <65: Refractory AML or AML relapse within six months of attaining
remission or AML relapse more than six months after achieving a remission, who cannot
achieve a second remission or Untreated subjects who develop AML after preexisting
hematologic disease or Secondary AML or high-risk MDS who either are not a candidate
for hypomethylating agents or who have failed one or more hypomethylating agent

- For subjects Age ≥65: De novo AML not candidates for induction chemotherapy or
Refractory AML or AML relapse within six months of attaining remission or AML relapse
more than six months after achieving a remission, who cannot achieve a second
remission or Untreated subjects who develop AML after preexisting hematologic disease
Secondary AML or high-risk MDS who either are not a candidate for hypomethylating
agents or who have failed one or more hypomethylating agent

- Life expectancy of at least 2 months

- Adequate Organ Function: Total bilirubin < 2.0 times the institutional Upper Limit of
Normal (ULN), Hepatic enzymes (AST, ALT ) ≤ 2.5 times the institutional ULN, Serum
Creatinine < 2.0 times the institutional ULN

- Ability to take oral medication (dasatinib must be swallowed whole)

- Concomitant Medications: Patient agrees to discontinue St. Johns Wort while receiving
dasatinib therapy (discontinue St. Johns Wort at least 5 days before starting
dasatinib). Patient agrees that IV bisphosphonates will be withheld for the 4 weeks
of dasatinib therapy due to risk of hypocalcemia.

- Age and Sex: Men and women, age 18-100. Women of childbearing potential (WOCBP) must
be using an adequate method of contraception to avoid pregnancy throughout the study
and for up to 30 days after the last dose of study drug to minimize the risk of
pregnancy. WOCBP include any woman who has experienced menarche and who has not
undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation,
or bilateral oophorectomy) or who is not post-menopausal. Post-menopause is defined
as: Amenorrhea that has lasted for >= 12 consecutive months without another cause, or
For women with irregular menstrual periods who are taking hormone replacement therapy
(HRT), a documented serum follicle-stimulating hormone (FSH) level of greater than 35
mIU/mL. Women who are using oral contraceptives, other hormonal contraceptives
(vaginal products, skin patches, or implanted or injectable products), or mechanical
products such as an intrauterine device or barrier methods (diaphragm, condoms,
spermicides) to prevent pregnancy, or who are practicing abstinence or where their
partner is sterile (eg, vasectomy) should be considered to be of childbearing
potential. WOCBP must have a negative serum or urine pregnancy test (minimum
sensitivity 25 IU/L or equivalent units of HCG) within 72 hours before the start of
the investigational product. A male subject of fathering potential must use an
adequate method of contraception to avoid conception throughout the study [and for up
to 30 days after the last dose of study drug] to minimize the risk of pregnancy. A
barrier method is recommended.

Exclusion:

- Sex and Reproductive Status: WOCBP who are unwilling or unable to use an acceptable
method to avoid pregnancy for the entire study period and for at least 4 weeks after
the last dose of study drug. Women who are pregnant or breastfeeding. Women with a
positive pregnancy test. Sexually active fertile men not using effective birth
control if their partners are WOCBP.

- Target Disease Exceptions: Subjects with a diagnosis of Acute Promyelocytic Leukemia,
Known or clinically suspected CNS involvement, HIV Positivity, A diagnosis of another
active malignancy with the exception of non-melanoma skin cancer or cervical cancer
in situ., Gastrointestinal conditions that could affect drug absorption including
post surgical states such as gastric bypass, History of psychiatric disorder which
may compromise compliance, Stem cell transplant within 60 days., Subjects who have
undergone stem cell transplant who are undergoing treatment or prophylaxis for Graft
versus host disease

- Medical History and Concurrent Diseases: Concurrent medical condition which may
increase the risk of toxicity, including: Pleural or pericardial effusion of any
grade, Cardiac Symptoms; any of the following will be considered for exclusion:
Uncontrolled angina, congestive heart failure or MI within (6 months), Diagnosed
congenital long QT syndrome, Any history of clinically significant ventricular
arrhythmias (such as ventricular tachycardia, ventricular fibrillation, or Torsades
de pointes), Prolonged QTc interval on pre-entry electrocardiogram (> 470 msec),
Subjects with hypokalemia or hypomagnesemia if it cannot be corrected prior to
dasatinib administration

- Physical and Laboratory Test Findings: Chronic diarrhea, Uncontrolled,
life-threatening infection that is not responding to antimicrobial therapy

- Allergies and Adverse Drug Reactions: History of allergic reaction to ATRA, History
of allergic reaction to dasatinib

- Prohibited Treatments and/or Therapies: Category I drugs that are generally accepted
to have a risk of causing Torsades de Pointes or prolonge QT interval including:
(Patients must discontinue drug 7 days prior to starting dasatinib) (See section
5.6.1.2) quinidine, procainamide, disopyramide, amiodarone, sotalol, ibutilide,
dofetilide, erythromycin, clarithromycin, chlorpromazine, haloperidol, mesoridazine,
thioridazine, pimozide, cisapride, bepridil, droperidol, methadone, arsenic,
chloroquine, domperidone, halofantrine, levomethadyl, pentamidine, sparfloxacin,
lidoflazine, azithromycin, citalopram, escitalopram, flecainide, mesoridazine,
sevoflurane. Potent inhibitors of CYP3A4 (see section 5.6.1.1 for more details).
Proton pump inhibitors and H2 inhibitors (see section 5.6.2.3). St. John's Wort (see
section 5.6.2.4). Medications that inhibit platelet function and anticoagulants (see
section 5.6.2.5). Currently receiving anticancer therapy. Use of hydroxyurea within 7
days prior to screening labs. Treatment with a an investigational agent within 30
days prior to the first dose of dasatinib/ATRA or planning to receive an
investigational agent during the study. Growth factors within 14 days prior to
screening labs

- Other Exclusion Criteria: Prisoners, or subjects who are involuntarily incarcerated.
Subjects who are compulsorily detained for treatment of either a psychiatric or
physical (eg, infectious disease) illness.