A Phase 3b, Multicenter, Open-Label, Single-Arm Study of Acalabrutinib (ACP-196) in Subjects with Chronic Lymphocytic Leukemia

1. Men and women >=18 years of age; 2. Diagnosis of CLL that meets published
diagnostic criteria: a. Monoclonal B-cells (either kappa or lambda light chain
restricted) that are clonally co-expressing >=1 B-cell marker (CD19, CD20, and
CD23) and CD5; b. Prolymphocytes may comprise <55% of blood lymphocytes; c.
Presence of >=5 × 10^9 B lymphocytes/L (5000/µL) in the peripheral blood (at any
point since the initial diagnosis); 3. Active disease per IWCLL 2018 criteria
that requires 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 (i.e., >=6 cm below
the left costal margin), progressive, or symptomatic splenomegaly. c. Massive
nodes (i.e., >=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. Lymphocyte doubling time may be obtained
by linear regression extrapolation of absolute lymphocyte count obtained at
intervals of 2 weeks over an observation period of 2 to 3 months. In
participants with initial blood lymphocyte counts of <30x109/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 (e.g., infections) should be excluded. e. Autoimmune anemia and/or
thrombocytopenia that is poorly responsive to standard therapy. f. B-symptoms
documented in the participants chart with supportive objective measures, as
appropriate, defined as >=1 of the following disease-related symptoms or signs
(please refer to protocol for related symptoms); 4. Must meet 1 of the
following criteria: a. Have received no prior therapy for treatment of CLL and
meets 1 of the following criteria: i. A score of >6 on the Cumulative Illness
Rating Scale (CIRS). ii. Creatinine clearance of 30 to 69 ml/min using the
Cockcroft-Gault equation. b. Have previously received therapy for CLL and have
either refractory or relapsed CLL. c. Have received prior BTKi therapy (i.e.,
defined as a participant who discontinued a BTKi for any reason except disease
progression) for CLL. d. Have either TN or R/R CLL and are receiving
concomitant vitamin K antagonists (e.g., coumadin). 5. ECOG performance status
of <=2; 6. Female subjects of childbearing potential (i.e., not surgically
sterile or postmenopausal) who are sexually active with a non-sterilized male
partner must use >=1 highly effective method of contraception from the time of
screening and must agree to continue using such precautions for 2 days after
the last dose of study treatment. Non-sterilized male participants who are
sexually active with a female partner of childbearing potential must use a male
condom plus spermicide during the study. 7. Fluorescence in situ hybridization
(FISH) results within 60 days before screening reflecting the presence or
absence of del(17p), del(13q), del(11q), and trisomy of chromosome 12 along
with the percentage of cells with the deletion, along with TP53 sequencing.
Participants must also have molecular analysis to detect IGHV mutation status
at any time point since diagnosis. 8. Participants 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.

1. Participants who have had disease progression while on a BTKi for any
malignant or nonmalignant condition. 2. Prior malignancy (other than CLL),
except for adequately treated basal cell or squamous cell skin cancer, in situ
cancer, early stage prostate cancer, or other cancer from which the participant
has been disease-free for >=2 years. 3. History of confirmed progressive
multifocal leukoencephalopathy. 4. Significant cardiovascular disease such as
symptomatic arrhythmias, congestive heart failure, or myocardial infarction
within 6 months before screening, or any Class 3 or 4 cardiac disease as
defined by the NYHA Functional Classification, or QTcF >480 msec at screening.
Note: participants with rate-controlled, asymptomatic atrial fibrillation are
allowed to enroll in the study. 5. Malabsorption syndrome, disease
significantly affecting gastrointestinal function, resection of the stomach,
extensive small bowel resection that is likely to affect absorption,
symptomatic inflammatory bowel disease, partial or complete bowel obstruction,
or gastric restrictions and bariatric surgery, such as gastric bypass. 6.
Evidence of active Richter's transformation. If Richter*s transformation is
suspected (i.e., LDH increased, asymmetric fast LN growth or clinical
suspicion), it should be ruled out with positron emission tomography-computed
tomography (PET-CT) and/or biopsy according to guidelines. 7. Central nervous
system (CNS) involvement by CLL. 8. Known history of human immunodeficiency
virus, serologic status reflecting active HBV or HCV infection, any
uncontrolled active systemic infection along with participants who are on
ongoing anti-infective treatment and participants who have received vaccination
with a live attenuated vaccine within 4 weeks before the first dose of study
intervention. a. Participants who are anti-HBc positive and who are anti-HBs
negative will need to have a negative hepatitis B virus PCR result before
enrollment. Those who are HBsAg positive or hepatitis B virus PCR positive will
be excluded. b. Participants who are HCV antibody positive will need to have a
negative HCV PCR result before enrollment. Those who are HCV PCR positive will
be excluded. 9. Uncontrolled autoimmune hemolytic anemia or idiopathic
thrombocytopenic purpura 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 or equivalent for longer
than 2 weeks). 10. History of stroke or intracranial hemorrhage within 6 months
before the first dose of study intervention. 11. History of bleeding diathesis
(e.g., hemophilia or von Willebrand disease). 12. Presence of a
gastrointestinal ulcer diagnosed by endoscopy within 3 months before Screening.
13. Major surgical procedure within 4 weeks before first dose of study
treatment. Note: Participants who have had major surgery, must have recovered
adequately from any toxicity and/or complications from the intervention before
the first dose of study treatment. 14. Requires treatment with proton-pump
inhibitors (e.g., omeprazole, esomeprazole, lansoprazole, dexlansoprazole,
rabeprazole, or pantoprazole). Subjects receiving proton-pump inhibitors who
switch to H2-receptor antagonists or antacids are eligible for enrollment in
this study. 15. All participants requiring or receiving anticoagulation with
warfarin or equivalent vitamin K antagonists (e.g., phenprocoumon) within 7
days before first dose of study treatment except those participants who will be
enrolled into the vitamin K antagonist cohort. 16. Absolute neutrophil count
<0.50 x 109/L or platelet count <30 x 109/L, unless proven due to CLL and
raised above the limits by granulocyte colony-stimulating factor therapy and/or
pooled platelet transfusion. 17. Total bilirubin >3.0 ULN; or AST or ALT >3.0 x
ULN. Exception will be for Gilbert syndrome; if an investigator feels that a
participants total bilirubin is elevated secondary to Gilbert*s, the
participant must have a documented unconjugated bilirubin being >80% of the
total bilirubin number. The investigator must also document that hemolysis has
been ruled out along with (near)-normal lactate dehydrogenase and haptoglobin.
18. Estimated creatinine clearance of <30 mL/min, calculated using the formula
of Cockcroft and Gault or by direct assessment (i.e., creatinine clearance or
EDTA clearance measurement). 19. Breastfeeding or pregnant.