Phase 2 Study of the Combination of Bruton's Tyrosine Kinase Inhibitor PCI-32765 and Rituximab in High-Risk Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma Patients

Inclusion Criteria:

1. 1.Patients must have a diagnosis of high-risk CLL/SLL and be previously treated withup to 3 lines of prior therapy. High-risk CLL and high-risk SLL is defined by thepresence of a 17p deletion or 11q deletion or TP53 mutation. Any CLL and SLL patientwho has a short remission duration of less than 3 years after prior first-linechemo-immunotherapy, such as the FCR regimen, also fulfills criteria of high-riskCLL/SLL, regardless of the presence or absence of cytogenetic abnormalities.

2. 2.CLL and SLL patients with 17p deletion or TP53 mutation will not be required to havereceived any prior therapy, given the poor outcome of CLL/SLL patients to standardfrontline chemo-immunotherapy, such patients will be eligible if they are untreated orif they have received up to 3 lines of prior therapy.

3. Patients must have an indication for treatment by 2008 IWCLL Criteria.

4. Patients age > 18 years at the time of signing informed consent. Understand andvoluntarily sign an informed consent. Be able to comply with study procedures andfollow-up examinations.

5. Eastern Cooperative Oncology Group (ECOG)/World Health Organization (WHO) performancestatus of 0-1.

6. Patients of childbearing potential must be willing to practice highly effective birthcontrol (e.g., condoms, implants, injectables, combined oral contraceptives, someintrauterine devices [IUDs], sexual abstinence, or sterilized partner) during thestudy and for 30 days after the last dose of study drug. Women of childbearingpotential include any female who has experienced menarche and who has not undergonesuccessful surgical sterilization (hysterectomy, bilateral tubal ligation, orbilateral oophorectomy) or is not postmenopausal. Post menopause is defined asfollows: Amenorrhea >/= 12 consecutive months without another cause and a documentedserum follicle stimulating hormone (FSH) level >35 mIU/mL; a male of childbearingpotential is any male that has not been surgically sterilized.

7. Adequate renal and hepatic function as indicated by all of the following: Totalbilirubin </=1.5 x institutional Upper Limit of Normal (ULN) except for patients withbilirubin elevation due to Gilbert's disease who will be allowed to participate; anAlanine (ALT) </=2.5 x ULN; and an estimated creatinine clearance (CrCl) of > 30mL/min, as calculated by the Cockcroft-Gault equation unless disease related.

8. Free of prior malignancies for 3 years with exception of currently treated basal cell,squamous cell carcinoma of the skin, or carcinoma in situ of the cervix or breast.

9. A Urine Pregnancy Test (within 7 days of Day 1) is required for women withchildbearing potential

Exclusion Criteria:

1. Pregnant or breast-feeding females.

2. Treatment including chemotherapy, chemo-immunotherapy , monoclonal antibody therapy,radiotherapy, high-dose corticosteroid therapy (more than 60 mg prednisone orequivalent daily), or immunotherapy within 21 days prior to enrollment or concurrentwith this trial.

3. Investigational agent received within 30 days prior to the first dose of study drug orhave previously taken PCI-32765. If received any investigational agent prior to thistime point, drug-related toxicities must have recovered to Grade 1 or less prior tofirst dose of study drug.

4. Systemic fungal, bacterial, viral, or other infection not controlled (defined asexhibiting ongoing signs/symptoms related to the infection and without improvement,despite appropriate antibiotics or other treatment).

5. Patients with uncontrolled Autoimmune Hemolytic Anemia (AIHA) or autoimmunethrombocytopenia (ITP).

6. Patients with severe hematopoietic insufficiency, as defined by an absolute neutrophilcount of less than 500/micro-L and/or a platelet count of less than 30,000/micro-L attime of screening for this protocol.

7. Any other severe concurrent disease, or have a history of serious organ dysfunction ordisease involving the heart, kidney, liver or other organ system that may place thepatient at undue risk to undergo therapy with PCI-32765 and rituximab.

8. Significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias,congestive heart failure, or myocardial infarction within 6 months of screening, orany Class 3 or 4 cardiac disease as defined by the New York Heart AssociationFunctional Classification.

9. Significant screening ECG abnormalities including left bundle branch block, 2nd degreeAV block type II, 3rd degree block, bradycardia, and QTc > 470 msec.

10. Any serious medical condition, laboratory abnormality, or psychiatric illness thatplaces the subject at unacceptable risk if he/she were to participate in the study.

11. History of stroke or cerebral hemorrhage within 6 months.

12. Evidence of bleeding diathesis or coagulopathy.

13. Major surgical procedure, open biopsy, or significant traumatic injury within 28 daysprior to Day 1, anticipation of need for major surgical procedure during the course ofthe study.

14. Minor surgical procedures, fine needle aspirations or core biopsies within 7 daysprior to Day 1. Bone marrow aspiration and/or biopsy are allowed.

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

16. Treatment with Coumadin. Patients who recently received Coumadin must be off Coumadinfor at least 7 days prior to start of the study.

17. Any chemotherapy (e.g., bendamustine, cyclophosphamide, pentostatin, or fludarabine),immunotherapy (e.g., alemtuzumab, or ofatumumab), bone marrow transplant, experimentaltherapy, or radiotherapy is prohibited during therapy on this study.

18. Use of medications known to prolong QTc interval or that may be associated withTorsades de Pointes (refer to Appendix F) are prohibited within 7 days of startingstudy drug and during study-drug treatment.

19. Requires treatment with strong CYP3A4/5 and/or CYP2D6 inhibitors.