Study of Venetoclax (ABT-199) Added to Ibrutinib in Patients With High-Risk Chronic Lymphocytic Leukemia (CLL)

Study Drug Administration:

If you are found to be eligible to take part in this study, you will receive the study drugs
in study cycles that are 4 weeks (28 days) long.

You will take ibrutinib 1 time every day while you are on study 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 with a
return to the normal schedule the following day. You should not take extra capsules on the
following day to make up for a missed dose.

You will also take tablets of venetoclax 1 time every day for the rest of the study. Each
dose of venetoclax will be taken at about the same time as ibrutinib with about 1 cup (8
ounces) of water, within 30 minutes after you finish eating a low-fat breakfast. Timing of
dosing can be adjusted, if necessary, after discussion with your doctor.

In order to lower the risk of side effects, you will start taking venetoclax at a low dose
and then it will be increased each week as directed by your doctor until you are taking the
full dose.

If you vomit within 15 minutes of taking venetoclax and all the tablets are still intact,
another dose may be taken. Otherwise, you should not take another dose. In cases where a dose
of venetoclax is missed or forgotten, you should take the dose as soon as possible, as long
as it is within 8 hours after the dose was planned to have been taken.

You will also be given standard drugs to help decrease the risk of side effects beginning 3
days before your first dose of venetoclax. You may ask the study staff for information about
how the drugs are given and their risks. You will also be instructed to drink at least 6 cups
of water every day beginning 2 days before you take venetoclax until 1 day after the first
dose.

Tumor Lysis Syndrome Monitoring:

Starting about 3 days before receiving your first dose of venetoclax (and continuing for at
least 5 weeks of treatment), you will be given a drug to lower the risk of a serious side
effect called Tumor Lysis Syndrome (TLS). TLS happens when cancer cells break down rapidly.
The break-down products enter the bloodstream and are not flushed out quickly enough.

You will need to drink lots of water (at least a half-gallon each day) starting 2 days before
your first dose.

You will have blood tests (about 2 tablespoons each time) before your dose of venetoclax.
Depending on your individual risk of TLS, you may need to be hospitalized for 2 nights to
monitor for TLS. If you are hospitalized, you will have blood tests (about 2 tablespoons each
time) 4, 8, 12 and 24 hours after your dose. Based on your test results, your study doctor
may have more instructions for you, and you may need to meet with a kidney doctor while you
are in the hospital. You may need to receive fluids by vein.

If you are not hospitalized for TLS monitoring, you will be monitored closely as an
outpatient. You will have blood tests (about 2 tablespoons) 6-8 hours and 24 hours after you
take your first dose of venetoclax in Week 1 and Week 2. Some patients may also need this
monitoring in Weeks 3-5. This decision will be made by the study doctor based on your
individual risk of TLS. Based on these test results, your study doctor may have more
instructions for you. You may need to be hospitalized or have further tests.

Study Visits:

Every week during Cycle 1, and at the start of Cycles 2, 3, and 4:

- You will have a physical exam.

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

At the end of Cycles 6, 12, 18 and 24, you will have CT, PET/CT or MRI scans to check the
status of the disease. If the disease is considered to be in "complete remission," your
treating doctor may decide you do not need these scans.

At the end of Cycles 6, 12, 18 and 24, you will have a bone marrow biopsy to check on the
status of the disease. Based on how the disease responds to treatment, your doctor may decide
that you do not need to have this bone marrow biopsy at Cycles 18 and 24.

On Day 1 of Cycles 7, 10, 13, 16, 19, 22 and at the end of Cycle 24:

- You will have a physical exam.

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

Physical exams and blood draws may be done more often if the doctor thinks they are needed.

Length of Treatment:

You may receive venetoclax for up to 96 weeks. You may continue receiving ibrutinib for as
long as the study doctor thinks it is in your best interest. You will no longer be able to
take the study drugs if the disease gets worse, if intolerable side effects occur, or if you
are unable to follow study directions.

Long-term follow-up:

After completion of the study, you will continue to see your doctor for routine medical care.
You will also be asked to participate in a separate leukemia department protocol (DR09-0223).
The purpose of this protocol is to determine how long patients live after receiving leukemia
treatment. On this study, if you are not having follow-up at MD Anderson, study staff will
contact you, via phone, email or MyMDAnderson every 6-12 months, to see how you are doing.
Phone calls will take approximately 5-10 minutes. If you agree, you will sign a separate
consent form for this study.

Inclusion Criteria:

1. Patients must have a diagnosis of CLL/CLL and EITHER Have high-risk cytogenetic
features or molecular features, defined as: del(17p), del(11q), mutated TP53, complex
metaphase karyotype (defined as >/=3 unrelated chromosomal abnormalities, present in
at least 2 metaphases on conventional, stimulated cytogenetic analysis) OR Have
developed a BTK or PLCG2 mutation, detected by sequencing and have not developed
disease progression during ibrutinib therapy as defined by IWCLL criteria (Appendix 1)
OR B2M has not normalized after 1y ibrutinib therapy or is elevated at the screening
*** Note: some patients treated with ibrutinib may no longer have detectable FISH,
karyotypic or molecular abnormalities after 12 months of therapy. These patients will
be eligible if they fulfill the above criteria on a bone marrow biopsy or peripheral
blood specimen taken within the 3 months prior to starting ibrutinib or at some time
during their ibrutinib therapy and analyzed at a CLIA-accredited laboratory.

2. Patients must have received at least 12 months of ibrutinib therapy and have
measurable CLL by at least one of the following: Absolute monoclonal lymphocyte count
> 4000/microL; OR - Measurable lymph nodes with at least one node >1.5 cm in diameter
on CT; OR - Bone marrow with >/= 30% lymphocytes on aspirate differential; OR -
Detectable CLL cells using a standardized flow cytometry assay for minimal residual
disease

3. Age 18 years or older.

4. Eastern Cooperative Oncology Group (ECOG) Performance Status
5. Patients must have adequate renal and hepatic function: i) Serum bilirubin upper limit of normal (ULN) or Serum creatinine clearance of >/= 50ml/min (calculated or measured) iv) ALT and AST

6. Adequate bone marrow function: i) Platelet count of greater than 20,000/µl, with no
platelet transfusion in prior 2 weeks ii) ANC >/=500/µl in the absence of growth
factor support unless due to compromised bone marrow production from CLL, indicated by
>/=80% CLL in marrow. iii) Hemoglobin >/=8mg/dL.

7. INR <1.5

8. Adequate cardiac function, as assessed by: - Absence of uncontrolled cardiac
arrhythmia. - Echocardiogram demonstrating LVEF >/=35%. - NYHA functional class
9. Ability to provide informed consent and adhere to the required follow-up.

10. Women of childbearing potential must have a negative serum or urine beta human
chorionic gonadotropin (beta-hCG) pregnancy test result within 7 days prior to the
first dose of study drugs and must agree to use 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. Women of non- childbearing potential are
those who are postmenopausal (defined as absence of menses for >/=1 year) or who have
had a bilateral tubal ligation or hysterectomy. Men who have partners of childbearing
potential must agree to use effective contraception, defined above, during the study
and for 30 days following the last dose of study drug.

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

Exclusion Criteria:

1. Richter transformation.

2. 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.

3. Major surgery, radiotherapy, chemotherapy, biologic therapy, immunotherapy,
experimental therapy within 3 weeks prior to the first dose of the study drug.

4. Grade 3 or 4 hemorrhage within the past 3 weeks.

5. Uncontrolled active infections (viral, bacterial, and fungal).

6. Females who are pregnant or lactating.

7. Known positive serology for human immunodeficiency virus (HIV).

8. Active hepatitis B infection (defined as the presence of detectable HBV DNA or HBe
antigen). Patients who are HBsAg or HBcAb positive are eligible, provided HBV DNA is
negative. These patients must have monthly monitoring of HBV DNA for the duration of
the study.

9. Active hepatitis C, defined by the detection of hepatitis C RNA in plasma by PCR.

10. Active, uncontrolled autoimmune phenomenon (autoimmune hemolytic anemia or immune
thrombocytopenia) requiring steroid therapy >20mg prednisone daily or equivalent,
within 7 days of starting venetoclax.

11. Received other investigational therapeutic agent for CLL/SLL within 21 days of
starting venetoclax.

12. Concurrent use of warfarin.

13. Received strong CYP3A inhibitors or strong CYP3A inducers within 7 days of starting
venetoclax.

14. Consuming grapefruit, grapefruit products, Seville oranges, or star fruit within 7
days of starting venetoclax.

15. Prior treatment with venetoclax or other Bcl-2 inhibitor.

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