Ibrutinib as Early Therapy in Chronic Lymphocytic Leukemia (CLL)

Study Drug Administration:

If you are found to be eligible to take part in this study, you will take ibrutinib by mouth
1 time every day. Each dose should be taken with about 1 cup (8 ounces) of water.

If you miss a dose of ibrutinib, it can be taken as soon as possible on the same day. You
should take your next dose as scheduled. If you forget to take a dose, do not take extra
capsules on the next day to "make up" the missed dose.

You will be given standard drugs, such as allopurinol or valacyclovir, to help decrease the
risk of side effects. You may ask the study staff for information about how the drugs are
given and their risks. If you have side effects, your dose of ibrutinib may be lowered or
temporarily stopped until you recover from the side effects.

Length of Treatment:

You may take ibrutinib for up to 2 years (24 cycles). If at the end of 2 years you are
benefitting from ibrutinib and the study doctor thinks it is in your best interest to
continue taking it, other treatment options will be discussed with you to allow you to
continue to take ibrutinib.

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.

Study Visits:

Each cycle is 28 days.

On Day 28 of Cycles 1-3 and then every 3 cycles after that until Cycle 24 (Cycles 6, 9, 12,
and so on):

- Blood (about 2 tablespoons) will be drawn for routine tests.

- You will have a physical exam.

- You will have an EKG.

On Day 28 of Cycles 1, 3, 6, 12, and 24, blood (about 3 tablespoons) will be drawn to test
for genetic mutations related to the disease. At Months 3, 6, and 12, additional blood (about
8 teaspoons) will be drawn for immune system testing.

On Day 28 of Cycles 6, 12, 18 and 24, you will have CT, MRI or PET/CT scan to check the
status of the disease. Depending on the results of the CT, MRI or PET/CT scans, you may not
need to have these scans repeated. The doctor will discuss this with you.

On Day 28 of Cycles 6, 12 and 24, you will have a bone marrow biopsy to check the status of
the disease.

If the doctor thinks it is needed or if the disease gets worse, some tests/procedures, such
as physical exams and blood draws for routine tests, may be repeated more often.

Long-term follow-up:

Every 3 months, during a regularly scheduled clinic visit (if you are still receiving care at
MD Anderson) or by phone (if you are receiving care outside of MD Anderson), you will be
asked how you are doing, if you are still taking ibrutinib, and if you have any side effects.
If called, this call should last about 5-10 minutes.

Inclusion Criteria:

1. Patients must be age >/=18 years at the time of informed consent, understand and
voluntarily sign an informed consent, and be able to comply with study procedures and
follow-up examinations.

2. No treatment indication according to IWCLL/NCI-WG (International Working Group in
Chronic Lymphocytic Leukemia/National Cancer Institute-Working Group) 2008 criteria

3. Estimated time to first treatment of 3 years or less according to MDACC nomogram

4. ECOG performance status of 0-2

5. Male and female subjects who agree to use both a highly effective method of birth
control (eg, implants, injectables, combined oral contraceptives, some intrauterine
devices [IUDs], complete abstinence , or sterilized partner) and a barrier method
(eg., condoms, vaginal ring, sponge, etc) during the period of therapy and for 30 days
after the last dose of study drug for females and 90 days for males. OR Female
subjects who are of non-reproductive potential (ie, post-menopausal by history - no
menses for >/=1 year; OR history of hysterectomy; OR history of bilateral tubal
ligation; OR history of bilateral oophorectomy)

6. Adequate hepatic and renal function as indicated by all of the following: Total
bilirubin bilirubin elevation due to Gilbert's disease or of non-hepatic origin who will be
allowed to participate, provided bilirubin is x ULN; and estimated creatinine clearance (CrCl) of > 30 mL/min, as calculated by the
Cockcroft- Gault equation.

7. PT/INR <1.5 x ULN and PTT (aPTT) <1.5 x ULN (unless abnormalities are unrelated to
coagulopathy or bleeding disorder).

8. Free of prior malignancies for 3 years with exception of patients diagnosed with basal
cell or non-metastatic squamous cell carcinoma of the skin, or carcinoma in situ of
the cervix or breast, who are eligible even if they are currently treated or were
treated and/or diagnosed in the past 3 years prior to study enrolment

9. Diagnosis of CLL/SLL that meets IWCLL diagnostic criteria

Exclusion Criteria:

1. Receipt of any prior therapy for CLL. Patients who have received "early intervention"
with INVAC-1 vaccine against hTERT will be eligible provided all of the following
exist: i) They had no response to the vaccine treatment (persistent CLL >1% in bone
marrow). ii) ≥3 months have elapsed since the last dose of vaccine. iii) No residual
toxicities attributable to the vaccine exist at the time of study enrollment. iv) The
patient does not meet IWCLL criteria for requiring treatment.

2. Richter Transformation

3. Active malignancy requiring systemic therapy, other than CLL, with the exception of:
adequately treated in situ carcinoma of the cervix uteri; adequately treated basal
cell carcinoma or localized squamous cell carcinoma of the skin; previous malignancy
confined and surgically resected (or treated with other modalities) with curative
intent.

4. Systemic anticoagulation with warfarin or other Vitamin K antagonists

5. Active and uncontrolled autoimmune hemolytic anemia (AIHA) or autoimmune
thrombocytopenia (ITP) requiring daily prednisone dose of >/=20 mg

6. Current and concurrent use of strong CYP3A4 inhibitors or inducers

7. Pregnant or breast-feeding females

8. Uncontrolled and active systemic fungal, bacterial, viral, or other infection (defined
as exhibiting ongoing signs/symptoms related to the infection and without improvement,
despite appropriate antibiotics or other treatment)

9. Any other severe concurrent disease, or history of serious organ dysfunction or
disease involving the heart, kidney, liver or other organ system that, in the
investigator's opinion, may place the patient at undue risk to undergo therapy with
ibrutinib

10. Currently active, clinically significant cardiovascular disease, such as uncontrolled
arrhythmia or Class 3 or 4 congestive heart failure as defined by the New York Heart
Association Functional Classification; or a history of myocardial infarction, unstable
angina, or acute coronary syndrome within 6 months prior to randomization

11. History of ischemic stroke within 6 months prior to enrollment

12. Evidence of bleeding diathesis or coagulopathy within 3 months (eg, von Willebrand's
disease or hemophilia

13. Any history of symptomatic intracranial hemorrhage

14. Major surgical procedure with 4 weeks of first dose of study drug; open biopsy, or
significant traumatic injury within 7 days prior to enrollment date; anticipation of
need for major surgical procedure during the course of the study

15. Minor surgical procedures, fine needle aspirations or core biopsies within 3 days
prior to enrollment date. Bone marrow aspiration and/or biopsy are allowed

16. Serious, non-healing wound, ulcer, or bone fracture

17. Vaccinated with live, attenuated vaccines within 4 weeks of first dose of study drug

18. Active, uncontrolled infection

19. Known history of human immunodeficiency virus (HIV) or active with hepatitis C virus
(HCV) or hepatitis B virus (HBV). Subjects who are positive for hepatitis B core
antibody, hepatitis B surface antigen, or hepatitis C antibody must have a negative
polymerase chain reaction (PCR) result before enrollment. Those who are PCR positive
will be excluded

20. Currently active, clinically significant hepatic impairment Child-Pugh class B or C
according to the Child Pugh classification (see Appendix L)