A Randomized, Multicenter, Open-Label, Non-Inferiority, Phase 3 Study of
ACP-196 Versus Ibrutinib in Previously Treated Subjects with High Risk
Chronic Lymphocytic Leukemia

1. Men and women >= 18 years of age.
2. ECOG performance status of 0 to 2.
3. Diagnosis of CLL that meets published diagnostic criteria (Hallek 2008):
oMonoclonal B-cells (either kappa or lambda light chain restricted) that
are clonally co-expressing >= 1 B-cell marker (CD19, CD20, or CD23) and
CD5.
oProlymphocytes may comprise <= 55% of blood lymphocytes.
oPresence of >= 5 x 10^9 B lymphocytes/L (5000 µL) in the peripheral
blood (at any point since diagnosis); this applies to CLL only.
4. Must have >= 1 of the following high-risk prognostic factors:
i. Presence of 17p del by central laboratory.
ii. Presence of 11q del by central laboratory.
5. Active disease meeting >= 1 of the following IWCLL 2008 criteria for
requiring treatment:
a. Evidence of progressive marrow failure as manifested by the development of,
or worsening of, anemia (hemoglobin < 10 g/dL) and/or thrombocytopenia
(platelets < 100,000/µL).
b. Massive (ie, >= 6 cm below the left costal margin), progressive, or
symptomatic splenomegaly
c. Massive nodes (ie, >= 10 cm in the longest diameter), progressive, or
symptomatic lymphadenopathy.
d. Progressive lymphocytosis with an increase of > 50% over a 2-month period or
a LDT of < 6 months. LDT may be obtained by linear regression extrapolation of
ALC obtained at intervals of 2 weeks over an observation period of 2 to 3
months. In subjects with initial blood lymphocyte counts of < 30 X 10^9/L
(30,000/µL), LDT should not be used as a single parameter to define indication
for treatment. In addition, factors contributing to lymphocytosis or
lymphadenopathy other than CLL (eg, infections) should be excluded.
e. Autoimmune anemia and/or thrombocytopenia that is poorly responsive to
standard therapy.
f. Constitutional symptoms documented in the subject*s chart with supportive
objective measures, as appropriate, defined as >= 1 of the following
disease-related symptoms or signs:
i. Unintentional weight loss >= 10% within the previous 6 months before
Screening.
ii. Significant fatigue (ie, ECOG performance status 2 or worse; inability to
work or perform usual activities).
iii. Fevers > 100.5°F or 38.0°C for >= 2 weeks before Screening without evidence
of infection.
iv. Night sweats for > 1 month before Screening without evidence of infection.
6. Must have received >= 1 prior therapies for CLL.
8. Meet the following laboratory parameters:
a. ANC >= 750 cells/µL (0.75 x 10^9/L) or >= 500 cells/µL (0.50 x 10^9/L) in
subjects with documented bone marrow involvement, and independent of growth
factor support 7 days before assessment.
b. Platelet count >= 30,000 cells/µL (30 x 10^9/L) without transfusion support 7
days before assessment. Subjects with transfusion-dependent thrombocytopenia
are excluded.
c. Serum AST/SGOT and ALT/SGPT <= 3.0 x ULN.
d. Total bilirubin <= 1.5 x ULN.
e. Estimated creatinine clearance (ie, eGFR using Cockcroft-Gault) >= 30 mL/min.
9. Able to receive all outpatient treatment, all laboratory monitoring, and
all radiologic evaluations at the institution that administers study drug
for the entire study.
10. Women who are sexually active and can bear children must agree to use
highly effective
forms of contraception while on the study and for 2 days after the last dose of
acalabrutinib or 90 days after the last dose of ibrutinib, whichever is longer.
11. Men who are sexually active and can beget children must agree to use highly
effective
forms of contraception during the study and for 2 days after the last dose of
acalabrutinib or 90 days after the last dose of ibrutinib, whichever is longer.
12. Men must agree to refrain from sperm donation during the study and for 2
days after the last dose of acalabrutinib or 90 days after the last dose of
ibrutinib, whichever is longer.
13. Must be willing and able to adhere to the study visit schedule, understand
and comply with other protocol requirements, and provide written informed
consent and authorization to use protected health information (in accordance
with national and local subject privacy regulations). Note vulnerable subjects,
as defined in the International Conference on Harmonisation (ICH) GCP, are not
allowed on this protocol (eg, prisoners or institutionalized subjects).

1. Known CNS lymphoma or leukemia.
2. Known prolymphocytic leukemia or history of, or currently suspected,
Richter*s syndrome.
3. Uncontrolled AIHA or ITP defined as declining hemoglobin or platelet count
secondary to autoimmune destruction within the screening period or requirement
for high doses of steroids (> 20 mg daily of prednisone daily or equivalent).
4. Prior exposure to ibrutinib or to a BCR inhibitor (eg Btk or PI3 kinase or
Syk inhibitors) or a BCL-2 inhibitor (eg, ABT-199).
5. Received any chemotherapy, external beam radiation therapy, anticancer
antibodies, or investigational drug within 30 days before first dose of study
drug.
6. Corticosteroid use > 20 mg within 1 week before first dose of study drug,
except as indicated for other medical conditions such as inhaled steroid for
asthma, topical steroid use, or as premedication for administration of study
drug or contrast. For example, subjects requiring steroids at daily doses > 20
mg prednisone equivalent systemic exposure daily, or those who are administered
steroids for leukemia control or white blood cell count lowering are excluded.
7. Prior radio- or toxin-conjugated antibody therapy.
8. Prior allogeneic stem cell or autologous transplant.
9. Major surgery within 4 weeks before first dose of study drug.
10. History of prior malignancy except for the following:
a. Malignancy treated with curative intent and with no evidence of active
disease present for more than 3 years before Screening and felt to be at low
risk for recurrence by treating physician
b. Adequately treated lentigo maligna melanoma without current evidence of
disease or adequately controlled non-melanomatous skin cancer
c. Adequately treated cervical carcinoma in situ without current evidence
of disease
11. Significant cardiovascular disease such as uncontrolled or symptomatic
arrhythmias, congestive heart failure, or myocardial infarction within 6
months of screening, or any Class 3 or 4 cardiac disease as defined by
the New York Heart Association Functional Classification, or QTc > 480
msec at screening.
12. Unable to swallow capsules or malabsorption syndrome, disease significantly
affecting gastrointestinal function, or resection of the stomach or small bowel
or gastric bypass, symptomatic inflammatory bowel disease, or partial or
complete bowel obstruction.
13. Uncontrolled active systemic fungal, bacterial, viral, or other infection
(defined as exhibiting ongoing signs/symptoms related to the infection and
without improvement, despite appropriate antibiotics or other treatment) or
ongoing intravenous anti-infective treatment.
14. Known history of infection with HIV.
15. Serologic status reflecting active hepatitis B or C infection. Subjects
with hepatitis B core antibody positive who are surface antigen negative or who
are hepatitis C antibody positive will need to have a negative PCR result
before randomization. Those who are hepatitis B surface antigen positive or
hepatitis B PCR positive and those who are hepatitis C PCR positive will be
excluded.
16. History of stroke or intracranial hemorrhage within 6 months before
randomization.
17. History of bleeding diathesis (eg, hemophilia, von Willebrand disease).
18. Requires or receiving anticoagulation with warfarin or equivalent vitamin K
antagonists (eg, phenprocoumon) within 7 days of first dose of study drug.
19. Requires treatment with a strong cytochrome CYP3A4 inhibitor/inducer.
20. Requires treatment with proton pump inhibitors (eg, omeprazole,
esomeprazole, lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole).
21. Breastfeeding or pregnant.
22. Concurrent participation in another therapeutic clinical trial.
23. Presence of a gastrointestinal ulcer diagnosed by endoscopy within 3
months before screening