A Phase II Study Using Ibrutinib and Short-Course Fludarabine in Previously Untreated Patients With Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL)

Chronic lymphocytic leukemia (CLL) and/or small lymphocytic lymphoma (SLL) are tumors of B
cells that often affect elderly patients. While the cause of CLL is still unclear, studies
have indicated critical factors required for the tumor cells. First, CLL cells grow and
survive because they receive signals through the B-cell receptor (BCR); and second, CLL cells
benefit from interactions with other cells, especially T cells.

The stimulation through the BCR can be reduced with ibrutinib, which is an oral drug that
selectively inhibits Bruton s tyrosine kinase (BTK). In clinical trials, ibrutinib
demonstrated safety and high response rates in patients with high-risk disease. Ibrutinib has
gained FDA approval as a treatment for CLL patients with 17p deletion and for those who had
at least one prior therapy. However, single-agent ibrutinib has limitations; the drug does
not eliminate all the tumor cells, and, with time, the tumor cells may become resistant.
Therefore, combination of ibrutinib with other drugs could be beneficial. Here we chose
fludarabine because it is a well-tolerated drug that has been used widely to treat CLL. Also,
fludarabine can kill both malignant B cells and T cells that support the growth of leukemia
cells. With this approach we hope to restore healthier immune system.

This study will investigate the safety and efficacy of ibrutinib combined with fludarabine.
This protocol is intended for previously untreated CLL patients. Ibrutinib will be given
daily until disease progression or intolerable side effects occur. Fludarabine will be given
only in cycles 3 and 4.

-INCLUSION CRITERIA:

1. Men and women with histologically confirmed disease as defined by the following:

- CLL: clonal B-lymphocytosis greater than or equal to 5,000 cells/microL .

- SLL: lymphadenopathy with the tissue morphology of CLL but that are not leukemic,
< 5,000 cells/microL.

- Immunophenotypic profile or immunohistochemistry read by an expert pathologist as
consistent with CLL. This will include CD5, CD19, and CD20 expression by the CLL
cells typically also with CD23 expression, but CD23 negative cases may be
included if there is an absence of t(11;14).

2. Active disease as defined by at least one of the following (IWCLL consensus criteria):

- Weight loss greater than or equal to 10% within the previous 6 months

- Extreme fatigue

- Fevers of greater than 100.5 F for greater than or equal to 2 weeks without
evidence of infection

- Night sweats for more than one month without evidence of infection

- Evidence of progressive marrow failure as manifested by the development of, or
worsening of, anemia and/or thrombocytopenia

- Massive or progressive splenomegaly

- Massive nodes or clusters or progressive lymphadenopathy

- Progressive lymphocytosis with an increase of >50% over a 2-month period, or an
anticipated doubling time of less than 6 months

3. Treatment naive CLL/SLL patients

-Treatment-naive CLL indicates no prior anti-CLL therapy. Anti-CLL therapy includes
chemotherapies, monoclonal antibodies, and targeted agents with known or reasonably
expected anti-leukemic activity.

4. Eastern Cooperative Oncology Group (ECOG) performance status of less than or equal to
2

5. ANC > 750/uL, platelets > 50,000/uL

6. Agreement to use acceptable methods of contraception during the study and for 90 days
after the last dose of study drug if sexually active and able to bear or beget
children

- Female subjects who are of non-reproductive potential (ie, post-menopausal by
history no menses for greater than or equal to 1 year; OR history of
hysterectomy; OR history of bilateral tubal ligation; OR history of bilateral
oophorectomy). Female subjects of childbearing potential must have a negative
serum pregnancy test upon study entry.

- 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, complete abstinence, or sterilized partner) and a barrier
method (e.g. condoms, vaginal ring, sponge, etc.) during the period of therapy
and for 90 days after the last dose of study drug

- Complete abstinence is a highly effective method only if defined as refraining
from heterosexual intercourse during the entire period of risk associated with
the study treatments. The reliability of sexual abstinence needs to be evaluated
in relation to the duration of the clinical trial and the preferred and usual
lifestyle of the subject.

7. Willing and able to participate in all required evaluations and procedures in this
study protocol including swallowing capsules without difficulty

8. Ability to understand the purpose and risks of the study and provide signed and dated
informed consent and authorization to use protected health information (in accordance
with national and local subject privacy regulations)

EXCLUSION CRITERIA:

- Transformed CLL, including Hodgkin and non-Hodgkin lymphoma

- Active autoimmune hemolytic anemia or thrombocytopenia

- Known bleeding disorders

- Impaired hepatic function: Total bilirubin greater than or equal to 1.5 times upper
limit of normal unless due to Gilbert s disease, AST/ ALT greater than or equal to 2.5
times institutional upper limit of normal unless due to infiltration of liver,
Child-Pugh class B or C

- Impaired renal function: estimated GFR < 30ml/min/1.73m(2) based on CKD-EPI

- Life-threatening illness, medical condition or organ system dysfunction which, in the
investigator s opinion, could compromise the subject s safety, interfere with the
absorption or metabolism of ibrutinib and fludarabine, or put the study outcomes at
undue risk

- Concomitant immunomodulatory therapy, chemotherapy, radiotherapy or experimental
therapy

- Active Hepatitis B or Hepatitis C infection

- HIV infection

- Female patients who are currently in pregnancy, or unwilling to use acceptable methods
of contraception or refrain from pregnancy if of childbearing potential or currently
breastfeeding. Male patients who are unwilling to follow the contraception
requirements described in this protocol.

- Psychiatric illness/social situations that would limit the patient s ability to
tolerate and/or comply with study requirements.

- Unable to understand the investigational nature of the study or give informed consent.

- Individuals < 18 years old

- Known hypersensitivity to any component of ibrutinib or fludarabine

- Requires concomitant anticoagulation with Coumadin (warfarin) or other vitamin K
antagonists.

- Prior malignancy, except for adequately treated basal cell or squamous cell skin
cancer, in situ cervical cancer, or other cancer from which the subject has been
disease-free for greater than or equal to 2 years or which will not limit survival to
< 2 years

- Malabsorption syndrome, disease significantly affecting gastrointestinal function, or
resection of the stomach or small bowel or ulcerative colitis, symptomatic
inflammatory bowel disease, or partial or complete bowel obstruction

- History of stroke or intracranial hemorrhage within 6 months before the first dose of
study drug

- Major surgery within 4 weeks of first dose of study drug

- Currently active, clinically significant cardiovascular disease such as uncontrolled
or symptomatic arrhythmias, Class 3 or 4 congestive heart failure as defined by New
York Heart Association Functional Classification, or a history of myocardial
infarction or unstable angina, or acute coronary syndrome within 6 months of
screening.

- Subjects who received a strong cytochrome P450 (CYP) 3A inhibitor within 7 days prior
to the first dose of ibrutinib or subjects who require continuous treatment with a
strong CYP3A inhibitor.