Nivolumab With Ibrutinib for Relapsed, Refractory or High-Risk Untreated Patients With Chronic Lymphocytic Leukemia (CLL)

Study Groups and Study Drug Administration:

If you are found to be eligible to take part in this study, you will be assigned to 1 of 2
study groups, depending on if you are already taking ibrutinib or not. If you are NOT already
taking ibrutinib, you will be assigned to Group 1. If you are already taking ibrutinib, you
will be assigned to Group 2.

All participants will receive nivolumab by vein over about 1 hour on Days 1 and 15 of Cycles
1-24.

If you are in Group 1, starting at Cycle 2, you will also begin to take ibrutinib by mouth 1
time each day at about the same time, about 2 hours after eating but 30 minutes before your
next meal. You should take your dose of ibrutinib with a cup (about 8 ounces) of water. Do
not open the capsules or dissolve them in water.

If you are in Group 2, you will continue to take the dose of ibrutinib that you are currently
taking.

Study Visits:

On Day 1 of all cycles:

- You will have a physical exam, including a neurological exam.

- Blood (about 2 tablespoons) will be drawn for routine tests. If the doctor thinks it is
needed, you may have this blood draw performed more often.

- During Cycles 2-4, urine will be collected for routine tests.

On Days 8, 15, and 22 of Cycles 1-6:

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

- On Day 15 of Cycle 1 only, urine will be collected for routine tests.

- If the doctor thinks it is needed, you will have a physical exam, including a
neurological exam. After Cycle 1, you will only have this physical exam on Day 15.

If you are in Group 1, on Day 28 of Cycle 1:

- You will have a bone marrow aspiration to check the status of the disease.

- You will have a CT or PET scan to check the status of the disease.

On Day 28 of Cycle 3 and then every 3 cycles after that for the first year (Cycles 6, 9, 12,
and so on) and then every 6 cycles after that:

- You will have a bone marrow aspiration to check the status of the disease.

- If the doctor thinks it is needed, you will have a CT or PET scan to check the status of
the disease.

On Day 1 of Cycles 7 and beyond:

- You will have a physical exam, including a neurological exam.

- Blood (about 2 tablespoons) will be drawn for routine tests and to check the status of
the disease.

- Every 3 cycles (Cycles 7, 10, 13, and so on), urine will be collected for routine tests.

Every 6 weeks, if you can become pregnant, blood (about 1 tablespoon) or urine will be
collected for a pregnancy test.

At any time that the doctor thinks it is needed, you may have blood draws, CT/PET scans,
and/or bone marrow aspiration/biopsies to check the status of the disease, while you are on
study.

Length of Study:

You may receive up to 24 cycles of nivolumab. You can continue to take ibrutinib as long as
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:

Within 30 days after your last dose of study drugs:

- You will have a physical exam, including a neurological exam.

- Blood (about 2-3 tablespoons) will be drawn for routine tests and to check the status of
the disease.

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

- If the doctor thinks it is needed, you will have a CT or PET scan to check the status of
the disease.

Long-Term Follow-Up:

About 1 month after your end-of-study visit, you will continue to have follow-up visits for
up to 1 year.

- You will have a physical exam 1 time each month.

- Blood (about 2-3 tablespoons) will be drawn for routine tests 1 time each month.

- Blood (about 1 tablespoon) will be drawn for antibody testing 1 time every 3 months.

- If the doctor thinks it is needed, you will have a bone marrow aspirate to check the
status of the disease every 3-6 months.

- If the doctor thinks it is needed, you will have a CT or PET scan to check the status of
the disease every 3-6 months.

If you start a new type of anti-CLL/SLL treatment during the follow-up period, you will stop
having these study visits.

Inclusion Criteria:

1. Patients will have a diagnosis of CLL or SLL, refractory to or relapsed after at least
one prior standard therapy or untreated with del(17p) by fluorescence in-situ
hybridization (FISH) (high-risk cytogenetics) and have an indication for treatment by
IWCLL 2008 criteria (Cohort 1) OR have been on ibrutinib for at least 9 months with
measurable persistent disease (absolute lymphocyte count (ALC) > 4K/muL, any lymph
node > 1.5 cm by CT scan, or > 30% lymphocytes on bone marrow aspirate differential)
(Cohort 2), OR patients will have a diagnosis of RT, refractory to and/or relapsed
after at least one prior standard therapy or untreated with del(17p) by FISH
(high-risk cytogenetics) (Cohort 3).

2. Age 18 years or older.

3. Eastern Cooperative Oncology Group (ECOG) Performance Status
4. Patients must have adequate renal and hepatic function: -- Total bilirubin upper limit of normal (ULN). -- For patients with Gilbert's disease, total bilirubin
up to
5. Females of childbearing potential must have a negative serum or urine beta human
chorionic gonadotrophin (Beta-hCG) pregnancy test result within 24 hours prior to the
first dose of treatment and must agree to use an effective contraception method during
the study and for 23 weeks following the last dose of the study drugs. Females of non-
childbearing potential are those who are postmenopausal greater than 1 year or who
have had a bilateral tubal ligation or hysterectomy. Males who have partners of
childbearing potential must agree to use an effective contraceptive method during the
study and for 31 weeks following the last dose of study drugs.

6. Patients or their legally authorized representative must provide written informed
consent.

Exclusion Criteria:

1. History of another primary invasive malignancy that has not been definitively treated
or in remission for at least 2 years. Patients with non-melanoma skin cancers or with
carcinomas in situ are eligible regardless of the time from diagnosis (including
concomitant diagnoses). If patients have another malignancy that was treated within
the last 2 years, such patients may be enrolled if the likelihood of requiring
systemic therapy for this other malignancy within 2 years is less than 10%, as
determined by an expert in that particular malignancy at MD Anderson Cancer Center and
after consultation with the Principal Investigator

2. Any major surgery, radiotherapy, cytotoxic chemotherapy, biologic therapy,
immunotherapy, immunomodulatory drugs, experimental therapy within 4 weeks prior to
the first dose of the study drugs. Note: Prior therapy with anti CD20 monoclonal
antibody, anti CD52 monoclonal antibody, and lenalidomide are allowed. For oral
targeted therapies (such as idelalisib, venetoclax), a washout of 3 days is allowed.

3. Significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias,
congestive heart failure, or myocardial infarction within 2 months of screening, or
any Class 3 or 4 cardiac disease as defined by the New York Heart Association
Functional Classification.

4. History of stroke or cerebral hemorrhage within 2 month.

5. Patients who have uncontrolled hypertension (defined as sustained systolic blood
pressure >/= 160 mmHg or diastolic >/= 100 mmHg).

6. Known evidence of active cerebral/meningeal CLL. Patients may have history of central
nervous system (CNS) leukemic involvement if definitively treated with prior therapy
and no evidence of active disease at the time of registration.

7. Active, uncontrolled autoimmune hemolytic anemia or immune thrombocytopenia requiring
steroid therapy.

8. Patients with autoimmune diseases are excluded: Patients with a history of
Inflammatory Bowel Disease (including Crohn's disease and ulcerative colitis) are
excluded from this study as are patients with a history of autoimmune disease (e.g.,
rheumatoid arthritis, systemic progressive sclerosis, systemic lupus erythematosus,
Wegener's granulomatosis).

9. Patients with previous allogeneic stem cell transplant (SCT) ) within 6 months or with
active acute or chronic graft-versus host disease are exclude. Patients must be off
immunosuppression for GVHD for at least 30 days before cycle 1 day 1.

10. Patients with organ allografts (such as renal transplant) are excluded.

11. History of interstitial lung disease or pneumonitis.

12. Patients who are on high dose steroids (>10mg daily of prednisone or equivalent) or
immune suppression medications. Note: Patients on high-dose steroids (doses >10mg/day
of prednisone or equivalent) or immune suppression medications are eligible provided
these drugs are discontinued at least 3 days prior to starting on the study drugs.

13. Patients with uncontrolled active infection (viral, bacterial, and fungal) are not
eligible.

14. Current or chronic hepatitis B or C infection, or known seropositivity for Human
Immunodeficiency Virus (HIV).

15. Patient is pregnant or breast-feeding.

16. Concurrent use of investigational therapeutic agent.

17. Malabsorption syndrome or other condition that precludes enteral route of
administration.

18. Concomitant use of warfarin or other Vitamin K antagonists.

19. Requires treatment with a strong cytochrome P450 (CYP) 3A inhibitor.

20. Other severe acute or chronic medical or psychiatric condition or laboratory
abnormality that in the opinion of the investigator may increase the risk associated
with study participation or investigational product administration or may interfere
with the interpretation of study results and/or would make the patient inappropriate
for enrollment into this study.