PCI-32765 for Special Cases of Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

CLL/SLL is a malignancy of B cells that predominantly affects the elderly population.
Diagnosis is typically made in adults over the age of 50 and more than half of the people
with CLL/SLL are over the age of 70. Elderly patients in particular have other comorbidities
that limit the tolerability of standard CLL/SLL chemoimmunotherapy regimens and they often
have inferior response to these particular regimens. In addition, those patients with a 17p
deletion also have inferior outcomes due to rapid progression of disease as well as
refractoriness to standard treatment regimens.

It is still unclear what leads to the development of CLL/SLL. However, recent studies
indicated that B cell receptor (BCR) signaling is an important contributor to the disease and
could be a target for therapy. Bruton s Tyrosine Kinase (Btk) is an enzyme required for BCR
signaling.

Ibrutinib is a potent and selective inhibitor of Bruton Tyrosine Kinase (Btk). In vitro
lymphoma models have demonstrated that ibrutinib inhibits Btk. Inhibition of Btk blocks
downstream BCR signaling pathways and thus prevents B cell proliferation. A phase 1 study of
ibrutinib shows activity in multiple lymphomas including CLL/SLL.

This study will investigate the efficacy of ibrutinib for patients with CLL/SLL in patients
that are older than 65 who are in need of therapy.This protocol is intended both for patients
who have been untreated and those who have undergone other therapies.

-INCLUSION CRITERIA:

1. Cohort 1: Treated and untreated patients age 65 or older and need for therapy

Cohort 2: Treated (maximum accrual n=16) and untreated (n=27, evaluable) patients at
least 18 years old with 17p deletion or p53 expression by immunohistochemistry or p53
mutation by sequencing analysis.

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

- B-lymphocytosis greater than 5000 cells/microL (may be less than 5000
cells/microL if lymphadenopathy is present with histologic confirmation of lymph
node involvement by SLL)

- Immunophenotypic profile 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 no
t11;14 translocation present.

3. Active disease as defined by at least one of the following:

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

- Extreme fatigue

- Fevers of greater than 100.5 degrees 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 greater than 50% over a 2 month
period, or an anticipated doubling time of less than 6 months

- Compensated autoimmune hemolysis

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

5. ANC greater than 500/microL, platelets greater than 30,000/microL

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

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:

1. Previous radiotherapy, radioimmunotherapy, biological therapy, chemotherapy, or
treatment with an investigational product fpr CCL treatement in the last 4 weeks (i.e.
intravenous immunoglobulin).

2. Transformed CLL

3. Autoimmune hemolytic anemia or thrombocytopenia requiring steroid therapy

4. Impaired hepatic function: Total bilirubin greater than or equal to 1.5 times upper
limit of normal unless dute to Gilbert's disease, AST/ ALT greater than or equal to
2.5 times institutional upper limit of normal unless due to infiltration of the liver.

5. Impaired renal funtion: Creatinine greater than or equal to 2.0 mg/dL or GFR less than
or equal to 50ml/min

6. 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 PCI-32765 PO, or put the study outcomes at undue risk

7. Concomitant immunotherapy, chemotherapy, radiotherapy, corticosteroids (at dosages
equivalent to prednisone > 20 mg/day), or experimental therapy

8. Active Hepatitis B infection

9. HIV infection

10. Female patients: Current pregnancy or unwilling to take oral contraceptives 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.

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

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

13. Individuals < 18 yrs old

14. Known hypersensitivity to any component of PCI-32765

15. Any prior therapy with PCI 32765 or any other BTK inhibitors.

16. Requires anticoagulation with warfarin.

17. Requires treatment with strong CY3A4/5 and/or CYP2D6 inhibitors (unless no alternative
is available).