Study Of Sorafenib Added To Busulfan And Fludarabine Conditioning Regimen In Patients With Relapsed/Refractory AML Undergoing Stem Cell Transplantation

Central Venous Catheter:

The chemotherapy you receive, some of the other drugs in this study, and the stem cell
transplant will be given by vein through a central venous catheter (CVC). A CVC is a sterile
flexible tube that will be placed into a large vein while you are under local anesthesia.
Some blood samples will also be drawn through your CVC. The CVC will remain in your body
during treatment. Your doctor will explain this procedure to you in more detail, and you will
be required to sign a separate consent form.

Study Groups:

If you are found to be eligible to take part in this study, you will be assigned to a dose
level of sorafenib based on when you join this study. Up to 4 dose levels of sorafenib will
be tested. At least 3 participants will be enrolled at each dose level. The first group of
participants will receive the lowest dose level. Each new group will receive a higher dose
than the group before it, if no intolerable side effects were seen. This will continue until
the highest tolerable dose of sorafenib is found.

All participants will receive the same dose level of busulfan and fludarabine.

Study Drug Administration:

For a stem cell transplant, the days before you receive your stem cells are called minus
days. The day you receive the stem cells is called Day 0. The days after you receive the stem
cells are called plus days.

On Days -24 through -5, you will take sorafenib as a tablet by mouth once or twice a day.
Your study doctor will explain how many tablets to take and when to take them. Your dose may
change if you experience side effects.

You will receive busulfan by vein over about 3 hours on 2 separate days as either an
outpatient in the clinic or as an inpatient in the hospital.

If you receive busulfan as an outpatient, you will receive busulfan by vein over about 3
hours on Days -20 and -13. You will be admitted to the hospital on Day -7 and will receive
fluids by vein as part of your standard care. You will rest on Days -12 through -8.

If you receive busulfan as an inpatient, you will be admitted to the hospital on Day -21 and
will receive fluids by vein as part of your standard care. You will receive busulfan by vein
over about 3 hours on Days -20 and -13. You will rest on Days -12 through -7.

Pharmacokinetic (PK) Testing:

About 11 samples of blood (about 1-2 teaspoons each time) will be drawn for PK testing at
time points before and after you receive your first dose of busulfan and on Day -6. The study
staff will tell you the blood testing schedule. PK testing measures the amount of study drug
in the body at different time points and will help the doctor decide your dose of busulfan
for Days -5 through -3.

A heparin lock line will be placed in your vein to lower the number of needle sticks needed
for these draws. If it is not possible for the PK tests to be performed for technical
reasons, you will be taken off study. The study doctor will discuss this with you.

On Days -6 through -3, you will receive busulfan by vein over 3 hours and fludarabine by vein
over 1 hour.

On Day 0, you will receive the stem cell transplant by vein.

On Days +3 and +4:

- You will receive cyclophosphamide by vein over 3 hours. Cyclophosphamide is given to
lower the risk of graft-versus-host disease (GVHD). GVHD is a condition in which
transplanted tissue, such as stem cells, attacks the transplant recipient's body.

- You will receive mesna by vein over 30 minutes every 4 hours for a total of 10 mesna
doses on Days +3 and +4. Mesna is given to lower the risk of side effects to the bladder
caused by cyclophosphamide.

Starting on Day +5, you will receive tacrolimus nonstop by vein until you are able to take it
by mouth to help lower the risk of GVHD. You will then take tacrolimus by mouth 2 times a day
for about 50 days. After that, your tacrolimus dose may be lowered if you do not have GVHD.
Your doctor will discuss this with you.

Starting on Day +5, you will receive MMF as a tablet by mouth 3 times a day for 90 days or
longer, if you have a matched unrelated donor.

Starting on Day +7, you will receive filgrastim as an injection under the skin 1 time a day,
until your blood cell levels are high enough. Filgrastim is given to help with the growth of
a type of healthy white blood cells that fight infection.

Starting between Day +30 and Day +120, you will take sorafenib as a tablet by mouth twice a
day for up to 1 year. Each dose should be taken without food, at least 1 hour before eating a
meal or at least 2 hours after eating. You should also take your dose of sorafenib with a cup
(about 8 ounces) of water. Your study doctor will explain how many tablets to take and when
to take them. Your dose may change if you experience side effects.

Length of Study:

You will be on study for up to 3 years after the transplant. You may be taken off study early
if the disease gets worse, if you have any intolerable side effects, or if you are unable to
follow study directions.

You should talk to the study doctor if you want to leave the study early. If you are taken
off study early, you still may need to return for routine follow-up visits after the
transplant, if your doctor thinks it is needed.

It may be life-threatening to leave the study after you have begun to receive the study drugs
but before you receive the stem cells.

Study Tests:

As part of standard care, you will remain in the hospital for about 3-4 weeks after the
transplant. While you are in the hospital, blood (about 2 teaspoons) will be drawn every day
to check for side effects, for routine tests, to check your blood counts, to check your
kidney and liver function, and to check for infections.

After you are sent home from the hospital, you must remain in the Houston area to be checked
for infections and other transplant side effects until about 3 months after transplant.
During this time, you will return to the clinic at least 1 time each week. At each visit,
blood (about 2 teaspoons) will be drawn for routine tests. After the first cycle, you may see
your local doctor for follow-up tests/procedures.

About 1, 3, 6, and 12 months after the transplant:

- You will have a physical exam and you will be checked for symptoms of GVHD.

- Blood (about 5 teaspoons) will be drawn to see how your body has reacted to the
transplant.

- If your doctor thinks it is needed, you will have a bone marrow aspiration to check the
status of the disease. To collect a bone marrow aspiration, an area of the hip or other
site is numbed with anesthetic, and a small amount of bone marrow is withdrawn through a
large needle.

Inclusion Criteria:

1. Age >/= 18 and
2. Patients with acute myeloid leukemia both flt3 positive and negative

3. HLA-identical sibling or 8/8 matched unrelated donor available

4. Life expectancy of at least 12 weeks (3 months)

5. Laboratory and diagnostic test parameters: Direct bilirubin transaminase (ALT) limit of normal and creatinine clearance >/= 50; Diffusing capacity for carbon
monoxide (DLCO) > 50% of predicted corrected for hemoglobin; LVEF >/= 50%.

6. Subjects must be able to understand and be willing to sign the written informed
consent form. A signed informed consent form must be appropriately obtained prior to
the conduct of any trial-specific procedure.

7. All acute toxic effects of any prior treatment have resolved to NCI-CTCAE v4.0 Grade 1
or less at the time of signing the Informed Consent Form (ICF).

8. Women of childbearing potential must have a negative serum pregnancy test performed
within 7 days prior to the start of study drug. Post-menopausal women (defined as no
menses for at least 1 year) and surgically sterilized women are not required to
undergo a pregnancy test.

9. Subjects (men and women) of childbearing potential must agree to use adequate
contraception beginning at the signing of the ICF until at least 30 days after the
last dose of study drug. The definition of adequate contraception will be based on the
judgment of the principal investigator or a designated associate.

10. Subject must be able to swallow and retain oral medication.

Exclusion Criteria:

1. Acute myeloid leukemia in first complete molecular remission and favorable risk
disease as defined by presence of t(8:21) or inv (16).

2. Patients with a comorbidity score > 3. The Principal Investigator is the final arbiter
of eligibility for comorbidity score > 3.

3. Uncontrolled hypertension (systolic pressure >140 mm Hg or diastolic pressure > 90 mm
Hg [NCI-CTCAE v4.0] on repeated measurement) despite optimal medical management.

4. Active or clinically significant cardiac disease including: Congestive heart failure -
New York Heart Association (NYHA) > Class II. Active coronary artery disease. Cardiac
arrhythmias requiring anti-arrhythmic therapy other than beta blockers or digoxin.
Unstable angina (anginal symptoms at rest), new-onset angina within 3 months before
randomization, or myocardial infarction within 6 months before randomization.

5. Evidence or history of bleeding diathesis or coagulopathy. Patients with bleeding due
to prior thrombocytopenia are permitted.

6. Subject with any pulmonary hemorrhage/bleeding event of NCI-CTCAE v4.0 Grade 2 or
higher within 4 weeks before randomization; any other hemorrhage/bleeding event of
NCI-CTCAE v4.0 Grade 3 or higher within 4 weeks before randomization.

7. Subjects with thrombotic, embolic, venous, or arterial cerebrovascular event
(including transient ischemic attacks) within 6 months of informed consent.

8. Subjects who have used strong CYP3A4 inducers (eg, phenytoin, carbamazepine,
phenobarbital, St. John's Wort [Hypericum perforatum], dexamethasone at a dose of
greater than 16 mg daily, or rifampin [rifampicin], and/or rifabutin) within 28 days
before randomization.

9. Subjects with any previously untreated or concurrent cancer except cervical cancer
in-situ, treated basal cell carcinoma, or superficial bladder tumor. Subjects
surviving a cancer that was curatively treated and without evidence of disease for
more than 3 years before randomization are allowed. All cancer treatments must be
completed at least 3 years prior to study entry (i.e., signature date of the informed
consent form).

10. Presence of a non-healing wound, non-healing ulcer, or bone fracture.

11. History of organ allograft. (Including corneal transplant).

12. Known or suspected allergy or hypersensitivity to any of the study drugs, study drug
classes, or excipients of the formulations given during the course of this trial.

13. Any malabsorption condition.

14. Women who are pregnant or breast-feeding.

15. Inability to comply with the protocol and/or not willing or not available for
follow-up assessments.

16. Any medical, psychological, or psychosocial condition which, in the investigator's
opinion, makes the subject unsuitable for trial participation.