Targeted Therapy in Treating Patients With Relapsed or Refractory Acute Lymphoblastic Leukemia or Acute Myelogenous Leukemia

PRIMARY OBJECTIVES:

I. To determine the clinical activity of kinase inhibitors using pre-clinical (in-vitro)
activity to select individual therapy.

SECONDARY OBJECTIVES:

I. To evaluate overall objective response rates (complete response plus partial response).

II. Determine overall survival (OS) and progression-free survival (PFS). III. Any changes in
transfusion requirements.

TERTIARY OBJECTIVES:

I. Prioritize active/aberrant kinase pathways using an in vitro inhibitor screen using
individual primary leukemia samples.

II. Measure "on target" in vivo kinase inhibition and signal transducer and activator of
transcription (STAT)-5 phosphorylation and correlate with response to treatment.

III. Perform next generation sequencing (whole exome sequencing) for complete mutational
analysis.

IV. Identify aberrant gene expression in primary leukemia samples from study subjects.

V. Evaluate pharmacokinetics for each individual kinase inhibitor during therapy.

OUTLINE: Patients are assigned to 1 of 5 treatment groups based on pre-clinical kinase
inhibitor activity.

GROUP I: Patients receive dasatinib orally (PO) once daily (QD) on days 1-28. Courses repeat
every 28 days in the absence of disease progression or unacceptable toxicity.

GROUP II: Patients receive nilotinib PO twice daily (BID) on days 1-28. Courses repeat every
28 days in the absence of disease progression or unacceptable toxicity.

GROUP III: Patients receive sunitinib malate PO QD on days 1-28. Courses repeat every 28
days in the absence of disease progression or unacceptable toxicity.

GROUP IV: Patients receive sorafenib tosylate PO BID on days 1-28. Courses repeat every 28
days in the absence of disease progression or unacceptable toxicity.

GROUP V: Patients receive ponatinib hydrochloride PO QD on days 1-28. 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:

- Patients with >= 18 years of age with relapsed/refractory leukemia with a confirmed
diagnosis of acute myelogenous leukemia (AML) or acute lymphoblastic leukemia (ALL)
who meet the following criteria:

- Age 18-64: Salvage treatment failures only - defined as relapsed or refractory
to after least 1 cycle of salvage therapy

- Age > 65: Refractory to or have relapsed after induction chemotherapy defined as
no response to initial therapy

- Given the clinical activity and use of hypomethylating agents in AML
patients, for all AML populations, initial therapy and salvage therapy may
include hypomethylating agents; furthermore, patients >= 65 with
hematologic malignancies including chronic myelomonocytic leukemia (CMML)
or myelodysplasia (MDS) that transform to acute leukemia while actively
receiving hypomethylating agents (i.e. decitibine or azacytidine) will be
considered induction failures and thus are eligible; for Philadelphia
positive (Ph+) ALL, initial therapy and salvage therapy may include
steroids and imatinib or dasatinib or nilotinib

- Primary patient samples must show in vitro kinase inhibitor sensitivity as determined
by the Oregon Health and Science University (OHSU) functional kinase inhibitor
screen; for OHSU patients, functional kinase inhibitor screening may be performed as
part of this study or through enrollment in eIRB4422 if the identical Food and Drug
Administration (FDA)/Clinical Laboratory Improvement Act (CLIA) approved assay is
used and a result is available within 2 weeks of starting drug treatment

- Have not received any leukemia treatment within 1 week prior to starting study drug;
corticosteroids (oral and systemic) can be administered up to 24 hours prior to first
administration of study drug; doses of steroids =< 20 mg of prednisone (or
equivalent) are permitted; hydroxyurea must be stopped 24 hours prior to initiation
of study drug

- Patients must have normal organ function as defined below:

- Serum creatinine < 2.0 x institutional upper limit of normal (ULN)

- International normalized ratio (INR) < 1.5 x institutional ULN

- Adequate hepatic function as defined by the following criteria:

- Total serum bilirubin =< 1.5 x upper normal limit (ULN), unless due to Gilbert's
syndrome

- Alanine aminotransferase (ALT) =< 2.5 x ULN

- Aspartate aminotransferase (AST) =< 2.5 x ULN

- Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)

- Discontinuation of anti-coagulants and anti-platelet drugs at least 7 days prior to
start of study drug; aspirin 81 mg is permitted as long as platelet count is > 50 and
there is no evidence of active bleeding or coagulopathy (INR > 1.5, fibrinogen > 150)

- No uncontrolled infections as determined by the investigator

- No uncontrolled thyroid disease (e.g. hyperthyroid/hypothyroidism)

- No active graft versus host disease (GVHD): patients with a history of stem cell
transplant are eligible but cannot have evidence of active GVHD as determined by the
investigator

- Must be able to take oral medication

- Women of childbearing potential must have a negative serum or urine pregnancy test
(sensitivity < 25 IU human chorionic gonadotropin (HCG)/L) within 72 hours prior to
the start of study drug

- Persons of reproductive potential must agree to use an adequate method of
contraception throughout treatment and for at least 4 weeks after study drug is
stopped; women of childbearing potential and men with a sexual partner of
childbearing potential must be advised of the importance of avoiding pregnancy during
trial participation and the potential risk factors for an unintentional pregnancy

- Ability to understand and the willingness to sign a written informed consent and
Health Insurance Portability and Accountability Act (HIPPA) document

- Ponatinib

- Female and male patients who are fertile must agree to use an effective form of
contraception with their sexual partners from randomization through 4 months
after the end of treatment

- Discontinuation of any medications known to contribute significantly to the risk
of QT prolongation at least 48 hours prior to start of study drug

- Serum lipase =< 1.5 x ULN

- Serum amylase =< 1.5 x ULN

- Dasatinib

- Normal corrected QT (QTc) interval on screening electrocardiogram (ECG)
evaluation, defined as < 450 msec

- Discontinuation of any medications known to contribute significantly to the risk
of QT prolongation at least 48 hours prior to start of study drug

- Serum Na, K, Mg, and total serum Ca or ionized Ca levels must be greater than or
equal to the institutional lower limit of normal; subjects with low K or Mg
levels, total serum Ca and/or ionized Ca must be replete for protocol entry

- Women of childbearing potential (WOCBP) must have a negative serum or urine
pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within
24 hours prior to the start of study drug

- Men who are sexually active with WOCBP must agree to follow instructions for
method(s) of contraception for the duration of treatment with study drug plus 90
days (duration of sperm turnover) for a total of 90 days post-treatment
completion

- Azoospermic males and WOCBP, who are not heterosexually active, are exempt from
contraceptive requirements; however, WOCBP must still under pregnancy testing as
described in this section

- Investigators shall counsel WOCBP and male subjects who are sexually active with
WOCBP on the importance of pregnancy prevention and the implications of
unexpected pregnancy; investigators shall advise WOCBP and male subjects who are
sexually active with WOCBP on the use of highly effective contraception; highly
effective methods of contraception have a failure rate of <1% when used
consistently and correctly

- At a minimum, subjects must agree to the use of two methods of contraception,
with one method being highly effective and the other method being either highly
effective or less effective as listed

- Nilotinib

- Normal QTc interval on screening ECG evaluation, defined as < 450 msec

- Discontinuation of any medications known to contribute significantly to the risk
of QT prolongation at least 48 hours prior to start of study drug

- Sorafenib

- Creatinine (Crt) < 1.5 X ULN

Exclusion Criteria:

- Patients may not receive concurrent chemotherapy, radiotherapy or immunotherapy, nor
have received any investigational agents within 7 days prior to drug sensitivity
screening

- Uncontrolled angina, > New York Heart Association (NYHA) class III congestive heart
failure or myocardial infarction (MI) within 6 months prior to start of study
treatment

- Diagnosed congenital long QT syndrome

- Any history of clinically significant ventricular arrhythmias (such as ventricular
tachycardia, ventricular fibrillation, or torsades de pointes)

- History of significant bleeding disorder unrelated to cancer

- Drugs that affect the cytochrome P450 family 3 subfamily A polypeptide 4 (CYP3A4)
system (inducers/inhibitors/substrates) are allowed but should be used with caution
depending on specific kinase inhibitor used; dietary supplements will be discouraged;
however, their use may be allowed on a case by case basis per the discretion of the
investigator after consultation with an oncology pharmacist

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements

- Pregnant or lactating women are excluded from this study

- Known human immunodeficiency virus (HIV)-positive patients are excluded from the
study because of possible risk of lethal infection hen treated with marrow
suppressive therapy

- Ponatinib

- History of acute pancreatitis within 1 year of study or history of chronic
pancreatitis

- History of alcohol abuse

- Uncontrolled hypertriglyceridemia (triglycerides > 450 mg/dL)

- Clinically significant, uncontrolled, or active cardiovascular disease,
specifically including, but not restricted to:

- Any history of myocardial infarction, stroke, or revascularization

- Unstable angina or transient ischemic attack within 6 months prior to start
of study treatment

- Congestive heart failure within 6 months prior to enrollment, or left
ventricular ejection fraction (LVEF) less than lower limit of normal per
local institutional standards within 6 months prior to enrollment

- History of clinically significant (as determined by the treating physician)
atrial arrhythmia

- Any history of ventricular arrhythmia

- Any history of venous thromboembolism including deep venous thrombosis or
pulmonary embolism

- Uncontrolled hypertension (diastolic blood pressure > 90 mm Hg; systolic > 140
mm Hg); patients with hypertension should be under treatment on study entry to
effect blood pressure control; taking medications that are known to be
associated with torsades de pointes

- Taking any medications or herbal supplements that are known to be strong
inhibitors of CYP3A4 within at least 14 days before the first dose of ponatinib

- Ocular toxicity present as measured during a comprehensive eye exam

- Dasatinib

- Known pulmonary arterial hypertension

- Patients may not have pleural or pericardial effusion of any grade

- Patients may not have clinically significant pleural or pericardial effusion per
provider discretion

- Uncontrolled hypertension: inability to maintain blood pressure below the limit
of 140/90 mgHg

- Any history of second or third degree heart block (may be eligible of the
subject currently has a pacemaker)

- Sorafenib

- Major surgery, open biopsy, or significant traumatic injury within 30 days

- Non-healing wound, ulcer, or bone fracture

- Thrombotic or embolic venous or arterial events, such as cerebrovascular

- Accident, including transient ischemic attacks, arterial thrombosis, deep vein

- Thrombosis and pulmonary embolism within the past 6 months

- Uncontrolled hypertension

- Active bleeding during screening

- Hypersensitivity to sorafenib