Personalized Kinase Inhibitor Therapy Combined With Chemotherapy in Treating Patients With Newly Diagnosed Acute Myeloid Leukemia and Acute Lymphoblastic Leukemia

PRIMARY OBJECTIVES:

I. Determine feasibility of using an in vitro small molecule inhibitor screen to select
kinase inhibitors to add to standard chemotherapy induction in AML or ALL.

SECONDARY OBJECTIVES:

I. Determine the safety and tolerability of the addition of the kinase inhibitors when added
to standard chemotherapy induction.

II. Evaluate overall objective response rates at completion of induction therapy.

III. Evaluate need for re-induction at day 14 (+/- 3 days) for AML. IV. Evaluate sensitivity
to kinase inhibitors using our in vitro small molecule inhibitor screen in newly diagnosed
AML/ALL.

V. Determine twelve-month overall survival.

TERTIARY OBJECTIVES:

I. Perform next-generation mutational analysis in primary leukemia samples from study
subjects at baseline to establish a panel of known mutations for each subject and at the time
of bone marrow recovery after induction chemotherapy to measure residual disease and evaluate
utility of next-generation sequencing as a method compared to flow cytometry for minimal
residual disease (MRD).

II. Evaluate pharmacokinetics for each individual kinase inhibitor. III. Determine if there
is a cytogenetic or other risk group that has a higher rate of treatment failure or inability
to obtain results from the small molecule inhibitor screen.

OUTLINE: Patients are assigned to 1 of 2 arms.

ARM I (AML): Patients receive cytarabine intravenously (IV) continuously over 24 hours on
days 1-7, and idarubicin IV over 30 minutes on days 1-3.

ARM II (ALL) CYCLE A: Patients receive cyclophosphamide IV over 3 hours twice daily (BID) on
days 1-3, vincristine sulfate IV on days 4 and 11, doxorubicin hydrochloride IV on day 4,
dexamethasone PO on days 1-4 and 11-14, and rituximab IV on day 1 and 11 (day 11 only of
course 1). Treatment repeats every 28 days for up to 4 courses in the absence of disease
progression or unacceptable toxicity.

ARM II (ALL) CYCLE B: Patients receive cytarabine IV over 2 hours BID on days 2-3,
methotrexate IV over 2-22 hours on day 1, methylprednisolone sodium succinate IV BID on days
1-3, leucovorin calcium IV every 6 hours until methotrexate level is < 0.05 uM and rituximab
IV on days 1 and 8. Treatment repeats every 28 days for up to 4 courses in the absence of
disease progression or unacceptable toxicity.

In all arms, based on the results of the kinase inhibitor assay, patients receive either
sorafenib tosylate PO BID, sunitinib malate PO daily, dasatinib PO daily, ponatinib
hydrochloride PO daily, ruxolitinib phosphate or idelalisib PO BID on days 8-28 in the
absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 4-6 weeks, and then for a
minimum of 1 year.

Inclusion Criteria:

- Patients must have histologically confirmed AML or ALL, excluding acute promyelocytic
leukemia (APL); for histological confirmation, a bone marrow biopsy and aspirate must
be reviewed at Oregon Health & Science University (OHSU)

- Patients must have newly diagnosed AML or ALL without previous treatment; hydroxyurea
will be allowed to control peripheral blast count as clinically indicated but would
need to be stopped prior to initiation of tyrosine kinase inhibitor [TKI]); all-trans
retinoic acid (ATRA) is permitted during the period prior to ruling out a diagnosis of
APL; previous radiation treatment is allowable; patients must be deemed eligible for
treatment with cytotoxic induction chemotherapy with cytarabine and idarubicin for AML
or hyper-cyclophosphamide, dexamethasone, doxorubicin, vincristine sulfate (CVAD) for
ALL; patients newly diagnosed with ALL must have received no prior treatment for their
ALL with the exception of steroids (i.e. prednisone, dexamethasone); intrathecal
methotrexate or cytarabine, allowed prior to and throughout the enrollment period for
AML and ALL

- Subjects must be aged between >= 18 years and =< 64 for AML and > 40 and =< 64 for ALL

- Eastern Cooperative Oncology Group (ECOG) performance status =< 2

- Total bilirubin < 2.0 x institutional upper limit of normal (ULN)

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and
alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x
institutional ULN and thought to be due to hepatocellular dysfunction

- Potassium > lower limit of normal (LLN) or correctable with supplements prior to first
dose of study medication

- Magnesium > LLN or correctable with supplements prior to first dose of study
medication

- Total calcium (corrected for serum albumin) >= LLN or correctable with supplements
prior to first dose of study medication

- Serum amylase and lipase =< 1.5 x institutional ULN

- International normalized ratio (INR) =< 2.0 or correctable to 2.0 with vitamin K
therapy

- Corrected QT (QTc) =< 450 msec. for men or QTc =< 470 msec. for women

- Creatinine < 2.0 x ULN

- No clinically significant uncontrolled infections as determined by investigator

- Patients must be able to take oral medications

- Persons of reproductive potential must agree to an adequate method of contraception
throughout treatment and for at least 4 weeks after study drug is stopped

- Women of childbearing potential must have a negative serum or urine pregnancy
test within 8 days prior to start of study drug administration

- Patients must be willing to accept blood product transfusions

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

- DRUG-SPECIFIC INCLUSION CRITERIA

- DASATINIB

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

- Women must not be breastfeeding

- WOCBP must agree to follow instructions for method(s) of contraception for the
duration of treatment with study drug, plus 30 days (duration of ovulatory cycle)
for a total of 30 days post-treatment completion

- 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 undergo pregnancy testing

- 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

Exclusion Criteria:

- Newly diagnosed AML patients who are identified with FLT3-ITD or tyrosine kinase
domain (TKD) point mutation in the codon for an aspartate (D835) or an isoleucine
(I836) residue

- Patients with a diagnosis of Philadelphia chromosome (Ph)+ ALL are not eligible

- Subjects who are currently receiving any other investigational agents

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to study agent or other agents used in the study

- Drugs that affect the cytochrome P450 family 3, subfamily A, polypeptide 4 (CYP3A4)
systems are allowed but should be used with caution depending on specific kinase
inhibitor used

- All outside study medications and supplements will be reviewed and monitored by the
inpatient pharmacy team; patients will be discouraged from taking herbals and
additional supplements

- Patients should not be prescribed concomitant medications that may contribute to
prolonged QTc without consultation with the chemotherapy pharmacist; additional ECGs
should be done at the investigator?s discretion to ensure the subject?s safety; drugs
that are generally accepted to increase the risk of Torsades de Pointes, include (but
not limited to):

- Quinidine, procainamide, disopyramide

- Amiodarone, ibutilide, dofetilide, sotalol

- Erythromycin, clarithromycin

- Chlorpromazine, mesoridazine, thioridazine, pimozide

- Cisapride, bepridil, droperidol, methadone, arsenic, chloroquine, domperidone,
halofantrine, levomethadyl, pentamidine, sparfloxacin, lidoflazine

- Left ventricular ejection fraction < 50%

- Uncontrolled intercurrent illness including but not limited to, symptomatic New York
Heart Association (NYHA) class III congestive heart failure, uncontrolled angina
pectoris, myocardial infarction or stroke within 6 months prior to enrollment, or
psychiatric illness/social situations that would limit compliance with study
requirements

- Patients with a known human immunodeficiency virus (HIV) diagnosis are excluded from
the study

- History of hypersensitivity to any of the kinase inhibitors included in this study

- Pregnant or lactating women are excluded from the study

- Diagnosed congenital long QT syndrome

- Any history of significant bleeding disorder unrelated to cancer, including any
congenital bleeding disorder or any acquired bleeding disorder within one year of
start of study

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

- Patients must not have clinically significant malabsorption syndrome or history

- All patients must discontinue anti-platelet agents or anticoagulants 7 days prior to
initiation of study drug

- All patients with unhealed wounds or fistulas should not be given vascular endothelial
growth factor (VEGF) inhibiting TKIs

- DRUG-SPECIFIC EXCLUSION CRITERIA

- PONATINIB

- Patients with cytogenetically ?favorable risk' AML (core-binding factor
leukemias) will not be enrolled on the ponatinib arm; testing with cytogenetics
and fluorescence in situ hybridization (FISH) can establish this subtype within 7
days of the diagnostic bone marrow biopsy

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

- Uncontrolled hypertriglyceridemia (triglycerides > 450 mg/dL)

- Any history of myocardial infarction, stroke, or revascularization

- Any history of venous thromboembolism including deep venous thrombosis or
pulmonary embolism with the exception of upper Extremity/Line associated
deep vein thrombosis (DVTs) which are adequately treated (line removed
and/or patient anti-coagulated)

- 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

- DASATINIB

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

- Known pulmonary arterial hypertension

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

- 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

- Upper Extremity/Line associated DVTs which are adequately treated (line removed
and/or patient anticoagulated) are eligible

- Uncontrolled hypertension

- Active bleeding during screening

- Hypersensitivity to sorafenib

- Idelalisib

- Ongoing drug-induced liver injury, chronic active hepatitis C (hepatitis C virus
[HCV]), chronic active hepatitis B (hepatitis B virus [HBV]), alcoholic liver
disease, non-alcoholic steatohepatitis, primary biliary cirrhosis, extrahepatic
obstruction caused by cholelithiasis, cirrhosis of the liver, portal
hypertension, or history of autoimmune hepatitis

- Ongoing symptomatic pneumonitis

- Ongoing inflammatory bowel disease or autoimmune colitis

- Ongoing cytomegalovirus (CMV) infection, treatment, or prophylaxis within the
past 28 days prior to the screening test for active CMV

- History of serious allergic reaction including anaphylaxis and epidermal
necrolysis

- Ruxolitinib

- Chronic active hepatitis C (HCV)