Acalabrutinib for the Treatment of Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

Inclusion Criteria:

• Men and women >= 18 years of age

• Diagnosis of CLL/SLL meeting criteria as defined by International Workshop onChronic Lymphocytic Leukemia (iWCLL) 2018 criteria

• CLL patients cardiac intolerant to current treatment with ibrutinib as defined by AFor other cardiac arrhythmias. Other ibrutinib-related intolerances will be excluded

• Eastern Cooperative Oncology Group (ECOG) performance status of =< 2

• Absolute neutrophil count (ANC) >= 1000/mm^3 (Independent of growth factor supportat screening unless due to marrow involvement by CLL/SLL and/or disease-relatedimmune thrombocytopenia. If cytopenias are due to disease in the bone marrow anydegree of cytopenias is allowed. Patients with active uncontrolled autoimmunecytopenias are excluded)

• Platelets >= 30,000/mm^3 (Independent of growth factor support at screening unlessdue to marrow involvement by CLL/SLL and/or disease-related immune thrombocytopenia.If cytopenias are due to disease in the bone marrow any degree of cytopenias isallowed. Patients with active uncontrolled autoimmune cytopenias are excluded)

• Total bilirubin =< 1.5 x upper limit of normal (ULN) (excepting Gilbert's syndrome) (at screening)

• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x ULN (atscreening)

• Creatinine clearance >= 30 mL/min/1.73m^2 (at screening)

• Using 24-hour creatinine clearance or modified Cockcroft-Gault equation

• Woman of childbearing potential (WOCBP) who are sexually active must use highlyeffective methods of contraception during treatment and for 2 days after the lastdose of acalabrutinib

• Willing and able to participate in all required evaluations and procedures in thisstudy protocol

• Ability to understand the purpose and risks of the study and provide signed anddated informed consent and authorization to use protected health information

Exclusion Criteria:

• Prior exposure to acalabrutinib for primary cohort and prior exposure to BTKinhibitor for pilot cohort

• Presence of C481S mutation or PCLG2 mutation

• Disease progression on ibrutinib

• History of prior malignancy that could affect compliance with the protocol orinterpretation of results, except for the following:

• Curatively treated basal cell carcinoma or squamous cell carcinoma of the skinor carcinoma in situ of the cervix or carcinoma in situ of the prostate at anytime prior to study

• Other cancers not specified above that have been curatively treated by surgeryand/or radiation therapy from which subject is disease-free for >= 3 yearswithout further treatment

• Clinically significant cardiovascular disease such as prior myocarditis, congestiveheart failure, prior documented myocardial infarction (i.e., not self-reported),known infiltrative cardiomyopathy (ex. cardiac sarcoidosis, cardiac amyloidosis,etc.) or any class 3 or 4 cardiac disease as defined by the New York HeartAssociation Functional Classification. Note: Subjects with controlled, asymptomaticatrial fibrillation can enroll on study

• Prior allogeneic stem cell transplantation

• Prior cardiac transplantation

• Systemic or non-cancer targeted anti-inflammatory medications (i.e., steroids)

• Contradictions to MRI: non-compatible metal implant, weight > 300 pounds (lbs.) (MRIscanner limit), severe claustrophobia, advanced or end-stage renal disease (ESRD) (contraindication to gadolinium), pregnancy, cognitive disabilities that may impairability to comply with instructions or provide informed consent

• Has difficulty with or is unable to swallow oral medication or has significant.gastrointestinal disease that would limit absorption of oral medication

• Known history of infection with HIV or any active significant infection (e.g.,bacterial, viral, or fungal) including subjects with positive cytomegalovirus [CMV]deoxyribonucleic acid [DNA] polymerase chain reaction [PCR])

• Known history of hypersensitivity or anaphylaxis to study drug(s) including activeproduct or excipient components

• Active bleeding or history of bleeding diathesis (e.g., hemophilia or von Willebranddisease)

• Uncontrolled AIHA (autoimmune hemolytic anemia) or ITP (idiopathic thrombocytopenicpurpura)

• Presence of a gastrointestinal ulcer diagnosed by endoscopy within 3 months beforescreening

• Requires treatment with a strong cytochrome P450 3A4 (CYP3A4) inhibitor/inducer. Theuse of strong CYP3A inhibitors within 1 week or strong CYP3A inducers within 3 weeksof the first dose of study drug is prohibited

• Requires or receiving anticoagulation with warfarin or equivalent vitamin Kantagonists

• Prothrombin time (PT)/international normalized ratio (INR) or activated partialthromboplastin time (aPTT) (in the absence of lupus anticoagulant) > 2 x ULN

• Requires treatment with proton pump inhibitors (e.g., omeprazole, esomeprazole,lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole). Note: Subjectsreceiving proton pump inhibitors who switch to H2-receptor antagonists or antacidsare eligible for enrollment to this study

• History of significant cerebrovascular disease/event, including stroke orintracranial hemorrhage, within 6 months before the first dose of study drug

• Major surgical procedure within 28 days of first dose of study drug. Note: If asubject had major surgery, they must have recovered adequately from any toxicityand/or complications from the intervention before the first dose of study drug

• Received a live virus vaccination within 28 days of first dose of study drug

• History of or ongoing confirmed progressive multifocal leukoencephalopathy (PML)

• Received any investigational drug within 30 days or 5 half-lives (whichever isshorter) before first dose of study drug

• Hepatitis B or C serologic status:

• Subjects who are hepatitis B core antibody (anti-HBc) positive and who arehepatitis B surface antigen (HBsAg) negative will need to have a negativepolymerase chain reaction (PCR) and must be willing to undergo DNA PCR testingduring the study to be eligible. Those who are HBsAg positive or hepatitis BPCR positive will be excluded

• Subjects who are hepatitis C antibody positive will need to have a negative PCRresult to be eligible. Those who are hepatitis C PCR positive will be excluded

• Breastfeeding or pregnant

• Concurrent participation in another therapeutic clinical trial