ACE-CL-309: This phase III trial is evaluating acalabrutinib and rituximab (two anti-cancer drugs), given in combination with idelalisib or bendamustine (chemotherapy), for the treatment of Chronic Lymphocytic Leukaemia (CLL)A Randomized, Multicenter, Open-Label, Phase 3 Study of Acalabrutinib (ACP-196) Versus Investigator's Choice of Either Idelalisib Plus Rituximab or Bendamustine Plus Rituximab in Subjects With R/R Chronic Lymphocytic Leukemia

Exclusion

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 or equivalent).
4. Prior exposure to a BCL-2 inhibitor (e.g., venetoclax/ABT-199) or a BCR inhibitor (e.g., BTK inhibitors or PI3K inhibitors). Prior bendamustine is allowed if Investigator's choice for treatment in Arm B is idelalisib with rituximab. Bendamustine retreatment is allowed if the prior response to bendamustine lasted > 24 months.
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 daily prednisone equivalent 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 transplant or prior autologous transplant within 6 months of first dose of study drug(s) or presence of graft-vs-host disease or receiving treatment for graft-vs-host disease.
9. Major surgical procedure within 30 days of first dose of study drug. Note: If a subject had major surgery, they must have recovered adequately from any toxicity and/or complications from the intervention before the first dose of study drug.

10. History of prior malignancy except for the following:

    1. Malignancy treated with curative intent and with no evidence of active disease present for more than 2 years before screening and felt to be at low risk for recurrence by treating physician.
    2. Adequately treated lentigo maligna melanoma without current evidence of disease or adequately controlled nonmelanomatous skin cancer.
    3. Adequately treated carcinoma in situ without current evidence of disease.
11. Significant cardiovascular disease such as uncontrolled or untreated 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 (calculated using Fridericia's formula: QT/RR^0.33) at screening. Exception: Subjects with controlled, asymptomatic atrial fibrillation during screening are allowed to enroll on study.
12. Malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach, or extensive small bowel resection that is likely to affect absorption, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction, or gastric restrictions and bariatric surgery, such as gastric bypass.
13. Received a live virus vaccination within 28 days of first dose of study drug.
14. Known history of infection with HIV or any uncontrolled active systemic infection (e.g., bacterial, viral, or fungal). For study sites in Germany: active infection with human immunodeficiency virus (seropositivity for HIV-1 or HIV-2 antibodies, and if positive, reactivity against the HIV-specific p24 antigen).
15. Active CMV infection (active viremia as evidenced by positive polymerase chain reaction [PCR] result for CMV DNA).

16. Serologic status reflecting active hepatitis B or C infection.

    1. Subjects who are anti-HBc positive and who are surface antigen negative will need to have a negative PCR result before randomization. Those who are HbsAg-positive or hepatitis B PCR positive will be excluded.
    2. Subjects who are hepatitis C antibody positive will need to have a negative PCR result before randomization. Those who are hepatitis C PCR positive will be excluded.
17. Ongoing, drug-induced liver injury, alcoholic liver disease, non-alcoholic steatohepatitis, primary biliary cirrhosis, ongoing extrahepatic obstruction caused by cholelithiasis, cirrhosis of the liver, or portal hypertension.
18. History of or ongoing drug-induced pneumonitis.
19. History of serious allergic reactions including anaphylaxis and toxic epidermal necrolysis.
20. History of stroke or intracranial hemorrhage within 6 months before first dose of study drug.
21. History of bleeding diathesis (e.g., hemophilia, von Willebrand disease).
22. Requires or receiving anticoagulation with warfarin or equivalent vitamin K antagonists (e.g., phenprocoumon) within 7 days of first dose of study drug.
23. Presence of a gastrointestinal ulcer diagnosed by endoscopy within 3 months before screening.
24. Requires treatment with a strong CYP3A inhibitor/inducer.
25. 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 to this study.
26. Breast feeding or pregnant.
27. Concurrent participation in another therapeutic clinical trial.
28. Prothrombin time/INR or aPTT (in the absence of a Lupus anticoagulant) > 2.0 x ULN. Exception: Subjects receiving warfarin are excluded, however, those receiving other anticoagulant therapy who have a higher INR/aPTT may be permitted to enroll to this study after discussion with the medical monitor.
29. History of confirmed progressive multifocal leukoencephalopathy (PML)