Acalabrutinib in Combination With Anti-CD20 and Venetoclax in Relapsed/Refractory or Untreated CLL/SLL/PLL

Inclusion Criteria:

Patients with a diagnosis of intermediate or high risk CLL (or variant immunophenotype),
SLL, or B-PLL by IWCLL 2008 criteria (48) who have:

- Previously received at least one therapy for their disease.

- Previously untreated disease and 65 years old OR under 65 years old and or refuse or
are ineligible for chemoimmunotherapy

All patients must satisfy one of the following criteria for active disease requiring
therapy:

- Evidence of marrow failure as manifested by the development or worsening of anemia or
thrombocytopenia

- Massive (≥ 6 cm below the costal margin), progressive or symptomatic splenomegaly

- Massive nodes (≥ 10 cm) or progressive or symptomatic lymphadenopathy

- Constitutional symptoms, which include any of the following:

- Unintentional weight loss of 10% or more within 6 months

- Significant fatigue limiting activity

- Fevers ≥100.5 degrees F for 2 weeks or more without evidence of infection

- Night sweats >1 month without evidence of infection

- Patients with a history of Richter's transformation are eligible if they now have
evidence of CLL only, with <10% large cells in the bone marrow.

- ECOG performance status ≤ 2

- Life expectancy of < 2 years or that would confound assessment of toxicity in this
study

- Must be ≥ 18 years of age

Exclusion Criteria:

- Any life-threatening illness, medical condition, or organ dysfunction which, in the
investigator's opinion, could compromise the subjects' safety, interfere with the
absorption or metabolism of acalabrutinib, or put the study outcomes at undue risk.

- Subjects with active cardiovascular disease not medically controlled or those who have
had myocardial infarction in the past 6 months, or corrected QT interval (QTc) ≥480
ms.

- Malabsorption syndrome, disease significantly affecting GI function, or resection of
the stomach or small bowel or gastric bypass, ulcerative colitis, symptomatic
inflammatory bowel disease, or partial or complete bowel obstruction.

- Grade ≥2 toxicity (other than alopecia) continuing from prior anticancer therapy
including radiation.

- History of a bleeding diathesis (eg, hemophilia, Von Willebrand disease).

- Uncontrolled autoimmune hemolytic anemia (AIHA) or idiopathic thrombocytopenia
purpura.

- History of stroke or intracranial hemorrhage within 6 months before the first dose of
study drug.

- Requires or receiving anticoagulation with warfarin or equivalent vitamin K
antagonists (eg, phenprocoumon) within 28 days of first dose of study drug.

- Requires treatment with proton-pump inhibitors (eg, omeprazole, esomeprazole,
lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole).

- Subjects with history of or ongoing drug-induced pneumonitis.

- Subjects with human immunodeficiency virus (HIV) or active infection with hepatitis C
virus (HCV) or hepatitis B virus (HBV) or any uncontrolled active systemic infection.

- Subjects who are known to have hepatitis B infection or who are hepatitis B core
antibody or surface antigen positive.