Medical conditions
1. Evidence of disease (such as severe or uncontrolled systemic diseases, including uncontrolled hypertension and renal transplant) that, in the investigator's opinion, make it undesirable for the patient to participate in the study or that would jeopardize compliance with the protocol \[e.g. a single score of 4 on one single category on the CIRS-G-Score (but not a cumulative score of 4)\].
2. Significant cardiovascular disease such as symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of randomization or any Class 3 or 4 cardiac disease as defined by the New York Heart Association Functional Classification, or LVEF \< 40%. Patients with controlled, asymptomatic atrial fibrillation are allowed to enroll on study.
3. Severe pulmonary dysfunction (CTCAE grade 3 or 4) unless associated with lymphoma.
4. Severe psychiatric or neurologic disease that, in the investigator's opinion, make it undesirable for the patient to participate in the study or that would jeopardize compliance with the protocol.
5. Persistent neuropathy CTCAE grade 3 or 4.
6. Refractory nausea and vomiting, inability to swallow acalabrutinib, or malabsorption syndrome; chronic severe gastrointestinal disease, gastric restrictions, or bariatric surgery such as gastric bypass; partial or complete bowel obstruction, or previous significant bowel resection that would preclude adequate absorption, distribution, metabolism, or excretion of study treatment.
7. History of prior malignancy that could affect compliance with the protocol or interpretation of results, except for the following:
1. Curatively treated localised basal cell carcinoma or localised squamous cell carcinoma of the skin or carcinoma in situ of the cervix or carcinoma in situ / low risk carcinoma of the prostate requiring only observation, as well as untreated low grade lymphoma except chronic lymphocytic leukemia.
2. Other cancers not specified above that have been curatively treated by surgery and/or radiation therapy from which patient is disease-free for ≥2 years (≥5 years for those treated with chemotherapy) without further treatment or which are not expected to limit survival to \< 2 years.
8. Received a live virus vaccination within 28 days of randomization.
9. Known history of infection with HIV.
10. Any active significant infection (e.g., bacterial, viral or fungal) as assessed by the investigator.
11. History of or ongoing confirmed progressive multifocal leukoencephalopathy (PML).
12. Serologic status reflecting active hepatitis B or C infection.
1. Patients who are hepatitis B core antibody (anti-HBc) positive and who are hepatitis B surface antigen (HBsAg) negative will need to have a negative PCR result before randomization and must be willing to undergo DNA PCR testing during the study. Those who are HBsAg-positive or hepatitis B PCR positive will be excluded.
2. Patients 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.
13. History of stroke or intracranial hemorrhage within 6 months before randomization.
14. History of clinically relevant bleeding diathesis (e.g., hemophilia, von Willebrand disease).
15. Major surgical procedure within 30 days before randomization. Note: If a patient had major surgery, they must have recovered adequately from any toxicity and/or complications from the intervention before the first dose of study drug.
16. Breastfeeding or pregnant women.
17. Current life-threatening illness, medical condition, organ system dysfunction, social, geographical or economic condition which, in the Investigator's opinion, could compromise the patient's safety or put the study at risk.
18. Diagnosis of primary central nervous system lymphoma or secondary central nervous system or meningeal involvement by lymphoma
19. Diagnosis of Richter's Transformation/transformed CLL Prior/Concomitant therapy
20. Requires or receiving anticoagulation with warfarin or equivalent vitamin K antagonists. Patients using therapeutic low molecule weight heparin, direct oral anticoagulants or low dose aspirin will be eligible. Switching from vitamin K antagonists to one of the allowed anticoagulants above prior to trial entry is permitted.
21. Requires treatment with a strong cytochrome P450 3A (CYP3A) inhibitor or inducer. The use of strong CYP3A inhibitors within 1 week or strong CYP3A inducers within 3 weeks of the first dose of study drug is prohibited. See details in section 9.12.1.
22. Prior exposure to a BTK inhibitor.
23. Prior anthracycline use ≥300 mg/m2.
24. Already initiated lymphoma therapy except for steroid (max. total dose of 1000mg), vincristine (max. 1 mg once) or rituximab (max. 375mg/m2) prephase.
25. Concurrent participation in another therapeutic clinical trial.
26. Requires treatment with proton-pump inhibitors (e.g., omeprazole, esomeprazole, lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole). Patients receiving proton pump inhibitors who switch to H2-receptor antagonists or antacids are eligible for enrolment into this study.
27. Received any investigational drug within 30 days or 5 half-lives (whichever is shorter) before first dose of study drug.