An Open-Label, Phase I/II Study of Nilotinib (Tasigna) and MEK-162 (ARRY-162) Used in Combination for Patients With Refractory or Advanced Chronic Myeloid Leukemia and Philadelphia Positive Acute Leukemia (Protocol CAMN107AUS41T)

Study Groups:

If you are found to be eligible to take part in this study, you will be assigned to a study
group based on when you join this study. Up to 5 groups of up to 6 participants will be
enrolled in Phase 1 of the study, and up to 60 participants will be enrolled in Phase 2.

If you are enrolled in Phase 1, the dose of nilotinib and MEK-162 you receive will depend on
when you joined this study. The first group of participants will receive the starting dose
combination level. The next group will receive a higher dose of MEK-162 than Group 1, if no
intolerable side effects were seen. If intolerable side effects are seen, the next group may
receive a lower dose level of nilotinib and/or MEK-162. This will continue until the highest
tolerable combination dose is found.

If you are enrolled in Phase 2, you will receive nilotinib and MEK-162 at the highest dose
that was tolerated in Phase 1.

Study Treatment:

You will take nilotinib and MEK-162 two times every day by mouth.

Participants enrolled in Phase 1 of the study will start taking MEK-162 on Day 1 and
nilotinib on Day 2.

Participants in Phase 2 of the study will be divided in 2 groups: one group will start
MEK-162 on Day 1 and nilotinib on Day 2, while the other group will start MEK-162 on Day 1
and nilotinib on Day 8. You will be placed in a Phase 2 treatment group based on the
characteristics of your disease type.

You will be given a drug diary and asked to write down what time you take the study drugs
every day. Bring in any unused study drugs and bottles to each study visit.

Each cycle is 28 days.

If the disease does not appear to get better after 1 or 3 cycles, you may be able to receive
a higher dose of the study drug as long as you are not already receiving the highest dose
planned for this study. The study doctor will tell you if you can receive a higher dose.

Study Visits:

On Days 1 and 8 of Cycle 1:

- You will have a physical exam.

- Blood (about 2-3 tablespoons) and urine will be collected for routine tests.

- You will have an EKG.

At the end of Cycle 1:

- You will have a physical exam.

- Blood (about 2-3 tablespoons) and urine will be collected for routine tests.

- You will have an EKG and either a MUGA scan or an ECHO.

- You will complete a questionnaire about how you are feeling.

- If the doctor thinks it is needed, you will have a bone marrow aspirate to check the
status of the disease.

At the end of Cycles 2, 3, and every 3 cycles after that (6, 9, 12, and so on):

- You will have a physical exam.

- Blood (about 2-3 tablespoons) and urine will be collected for routine tests.

- You will have an EKG.

- You will complete a questionnaire about how you are feeling.

At the end of Cycles 2, 3, 6, 9, and 12, blood (about 3-4 tablespoons each time) will be
drawn for tests to check how the disease is responding to therapy. If the doctor thinks it is
needed, these tests may be performed more often.

Every 8-12 weeks, you will have a MUGA scan or an ECHO.

You will have an eye exam by an eye doctor at the end of Cycles 2, 3, 6, 9, and 12, and then
every 3 months after that until the End of Study Visit.

You will have blood draws and/or bone marrow aspirations at any time that the doctor thinks
it is needed while you are on study.

Length of Study:

You can take up to 12 cycles of nilotinib and MEK-162 on study. If the disease responds a
certain way (called a hematological response) while you are on study, you may be able to
continue taking the study drugs longer than 12 months, as long as the doctor thinks you are
benefiting from the treatment. Even if the disease has not responded in this way, you may be
able to continue taking the study drugs if the doctor thinks it is in your best interest. You
will no longer be able to take the study drug if the disease gets worse, if intolerable side
effects occur, or if you are unable to follow study directions.

Your participation on the study will be over after the follow-up visits.

End-of-Study Visit:

If you come off study before the end of Cycle 12, the following tests and procedures will be
performed:

- You will have a physical exam.

- Blood (about 2-3 tablespoons) and urine will be collected for routine tests.

- You will have an EKG and either an ECHO or a MUGA scan.

- You will have an eye exam by an eye doctor.

- You will complete a questionnaire about how you are feeling.

- If the doctor thinks it is needed, you will have a bone marrow aspirate to check the
status of the disease.

If you come off study at the end of Cycle 12, you will not have the End of Study visit.

Follow-Up:

You will be called about 30 days after you go off study and asked if you have had any side
effects and/or any new treatment(s). This call will last about 5 minutes.

This is an investigational study. Nilotinib is FDA approved and commercially available to
treat CML and philadelphia-positive acute leukemia. MEK-162 is not FDA approved or
commercially available. It is currently being used for research purposes only. The
combination of nilotinib and MEK-162 to treat CML and Philadelphia-positive acute leukemia is
investigational. The study doctor can explain how the study drugs are designed to work.

Up to 90 patients will take part in this study. All will be enrolled at MD Anderson Cancer
Center.

Inclusion Criteria:

1. Patients 18 years of age or older with advanced CML (CML-AP, CML-BP and Philadelphia
chromosome-positive acute leukemia) or refractory chronic phase CML are eligible, as
defined as follows: The phase I portion of the study will be conducted first in
advanced phase (accelerated phase CML, blast phase CML or Philadelphia-positive acute
leukemia) patients. Once MTD is identified, a cohort of 6 patients with CML chronic
phase who have failed prior therapy with at least two tyrosine kinase inhibitor will
be treated at the MTD to determine if this dose is also acceptable for chronic phase
patients. The phase II will be conducted in two treatment arms as follows: Treatment
Arm A (Advanced phase disease) and treatment Arm B (Therapy for CP-CML
refractory/resistant/suboptimally responding to at least two prior TKI's)

2. (Cont - Inclusion Criteria #1) CML-AP is defined by the presence of one of the
following: a. 15-29% blasts in peripheral blood (PB) or bone marrow (BM), b.>20%
basophils in PB or BM, c.>30% blasts plus promyelocytes (with blasts <30%) in PB or
BM, d.<100 x109/L platelets unrelated to therapy, or Clonal cytogenetics evolution
(i.e., the presence of cytogenetic abnormalities other than the Philadelphia
chromosome) except if only present at the time of diagnosis and not associated with
other features of accelerated phase. CML-BP is defined by the presence of >/=30%
blasts in the bone marrow and/or peripheral blood or the presence of extramedullary
disease, with myeloid or lymphoid blast morphology. Philadelphia-chromosome acute
leukemias are eligible and defined by >/=20% blasts in the peripheral blood or bone
marrow at the time of diagnosis.

3. Patients with advanced phase CML or acute leukemia must have failed at least one prior
TKI. Patients with chronic phase CML must have failed, have resistance or suboptimal
response to at least two tyrosine kinase inhibitors, or have intolerance to two prior
tyrosine kinase inhibitors. For patient with prior intolerance, they should have
received at least 2 TKI and experienced intolerance to one TKI and
resistance/suboptimal

4. (Cont - Inclusion Criteria #3) a. Failure to tyrosine kinase inhibitors will be
defined per European-Leukemia-Net (ELN) recommendations b.Resistance or suboptimal
response to at least two prior Abl-kinase inhibitor, specifically: i.Chronic-phase
with resistance to imatinib, dasatinib, nilotinib, bosutinib or ponatinib defined as
1. Loss of CCyR at any time or failure to achieve CCyR after >/=18 months 2. Loss of
MCyR at any time or failure to achieve PCyR after >/=12 months 3. Failure to achieve
any CyR (ie, >/= 65% Ph+) after >/= 6 months 4. Hematologic relapse or failure to
achieve CHR after >/=3 months ii. Chronic-phase with suboptimal response to imatinib,
defined as 1. Failure to achieve PCyR after >/= 6 months 2. Failure to achieve CCyR
after >/=12 months iii. Chronic-phase with suboptimal response to nilotinib,
bosutinib, dasatinib or ponatinib, defined as 1. Failure to achieve PCyR after >/= 3
months 2. Failure to achieve CCyR after >/= 6 months of therapy

5. Patients with cytogenetic BCR-Abl variants and additional chromosomal abnormalities
('clonal evolution') will be eligible. Cytogenetics to be performed, but results are
not required to start therapy in patients with hematologic progression

6. Patients who have failed nilotinib, including those who are refractory to nilotinib at
any dose or have relapsed on nilotinib at any dose will be eligible for the study.
Patients currently on nilotinib will continue on their prescribed dose of nilotinib
and MEK-162 will be added based on the current cohort level in phase I or at the
established MTD in phase II. In the instance the nilotinib dose is greater than the
current cohort (in phase 1) or the MTD (in phase 2) patients will be dose reduced to
the dosage as prescribed by protocol and then dose escalated as allowed in protocol at
the PIs discretion.

7. For the phase I portion of the study, patients who had received prior therapy with
nilotinib should have been able to tolerate the dose equivalent to the starting dose
of nilotinib in the dose level at which the patient is being entered. Patients who
previously received nilotinib but never at the dose being proposed are eligible
provided they tolerated the maximum dose they were prescribed with no grade 3 or 4
toxicity not responding to optimal management.

8. Patients must have been off all prior therapy for CML for 2 weeks prior to start of
study therapy and recovered from the toxic effects of that therapy. Exceptions to
these are hydroxyurea and TKIs (including but not limited to imatinib, nilotinib,
dasatinib, ponatinib and bosutinib), which should be discontinued ≥48 hrs prior to the
start of therapy. Patients who are receiving nilotinib prior to enrollment do not have
to discontinue this agent prior to start of study therapy

9. Eastern Cooperative Oncology Group (ECOG) performance status
10. Men and women of childbearing potential should practice effective methods of
contraception. Men and women of childbearing potential are defined as: a male that has
not been surgically sterilized or female that has not been amenorrheic for at least 12
consecutive months or that has not been surgically sterilized. Patients must use birth
control during the study and for 3 months after the last dose of study drug if they
are sexually active.

11. Adequate organ function: Serum creatinine /=60
mL/min, Direct bilirubin Alanine aminotransferase (ALT) involvement.)

12. Adequate cardiac function: left ventricular ejection fraction (LVEF) >/= 50% as
determined by a multigated acquisition (MUGA) scan or echocardiogram, QTc interval 480 ms;

13. Women of childbearing potential must have a pregnancy test at screening.

14. Signed informed consent.

Exclusion Criteria:

1. Impaired cardiac function including any one of the following: a. Inability to monitor
the QT interval on ECG b. Congenital long QT syndrome or a known family history of
long QT syndrome. c. Clinically significant resting brachycardia (<45 beats per
minute) d. QTc > 480 msec on baseline ECG. If QTc >450 msec and electrolytes are not
within normal ranges, electrolytes should be corrected and then the patient
re-screened for QTc e. Impaired cardiovascular function or clinically significant
cardiovascular diseases, including any of the following: History of acute coronary
syndromes (including myocardial infarction, unstable angina, coronary artery bypass
grafting, coronary angioplasty, or stenting) <6 months prior to screening, Symptomatic
chronic heart failure, history or current evidence of clinically significant cardiac
arrhythmia and/or conduction abnormality <6 months prior to screening except atrial
fibrillation and paroxysmal supraventricular tachycardia

2. History of Gilbert's syndrome.

3. Uncontrolled arterial hypertension despite medical treatment

4. Prior therapy with a MEK- inhibitor

5. History or current evidence of retinal vein occlusion (RVO) or current risk factors
for RVO (e.g. uncontrolled glaucoma or ocular hypertension, history of hyperviscosity
or hypercoagulability syndromes)

6. History of retinal degenerative disease;

7. Patients with washout period < 6 weeks from the last dose of ipilimumab or other
immunotherapy

8. Known positive serology for HIV, active hepatitis B, and/or active hepatitis C
infection

9. Patients who have neuromuscular disorders that are associated with elevated CK (e.g.,
inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal
muscular atrophy)

10. Patients who are planning on embarking on a new strenuous exercise regimen after first
dose of study treatment. Muscular activities, such as strenuous exercise, that can
result in significant increases in plasma CK levels should be avoided while on MEK162
treatment

11. Patients currently receiving treatment with strong CYP3A4 inhibitors who cannot
discontinue such treatment or be switched to a different medication prior to starting
study drug are excluded from study entry. Strong CYP3A4 inhibitors include the
following medications: itraconazole, ketoconazole, miconazole, voriconazole;
amprenavir, atazanavir, fosamprenavir, indinavir, nelfinavir, ritonavir;
ciprofloxacin, clarithromycin, diclofenac, doxycycline, enoxacin, isoniazid, ketamine,
nefazodone, nicardipine, propofol, quinidine, telithromycin.

12. Patients receiving treatment with any medications that have the potential to prolong
the QT interval who cannot discontinue such treatment or be switched to a different
medication prior to starting study drug are excluded from the study entry. A list of
anti-arrhythmic drugs and other drugs that may prolong the QT interval is added in
protocol section 8.5 (page 53).

13. Impaired gastrointestinal (GI) function or active GI disease that may significantly
alter the absorption of study drug in the opinion of the treating physician (e.g.,
active ulcerative diseases, uncontrolled nausea, uncontrolled vomiting, uncontrolled
diarrhea, active malabsorption syndrome, small bowel resection within last 1 year or
gastric bypass surgery within last 1 year).

14. Another active primary malignant disease, which requires systemic treatment
(chemotherapy or radiation)

15. History of significant congenital or acquired bleeding disorder unrelated to cancer

16. Major surgery within 4 weeks prior to Day 1 of the study or who have not recovered
from prior surgery.

17. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a
female after conception and until the termination of gestation, confirmed by a
positive human chorionic gonadotropin (hCG) laboratory test

18. Women of child-bearing potential, defined as all women physiologically capable of
becoming pregnant, unless they are using highly effective methods of contraception
throughout the study and for 3 months after study drug discontinuation. Highly
effective methods of contraception are further defined.

19. Patients who are eligible, willing and able to receive an allogeneic stem cell
transplant within 6 weeks are not eligible.

20. Sexually active males unless they use a condom during intercourse while taking the
drug and for 3 months after stopping treatment and should not father a child in this
period. A condom is required to be used also by vasectomized men in order to prevent
delivery of the drug via seminal fluid;

21. History of non-compliance to medical regimens or inability to grant consent.