Acalabrutinib for the Treatment of Relapsed/Refractory Primary or Secondary CNS Lymphomas

Inclusion Criteria

• Willing and able to participate in all required evaluations and procedures in this study protocol, including swallowing capsules and tablets without difficulty
• Ability to understand the purpose and risks of the study and provide signed and dated informed consent and authorization to use protected health information (in accordance with national and local patient privacy regulations)
• Age >= 18 years at the time of consent
• Subject has adequate performance status as defined by Eastern Cooperative Oncology Group (ECOG) of =< 2. (Note: Performance status can be assessed after administration of corticosteroids)
• Subject has histological confirmation of biopsy-proven CNS lymphoma OR MRI findings consistent with CNS lymphoma if biopsy is not possible (due to inaccessible location). Subjects with intra-ocular lymphoma will not be excluded as long as there is also parenchymal disease
• Subject has B-cell Non-Hodgkin lymphoma
• Subject has no evidence of systemic involvement of lymphoma confirmed by CT or PET-CT imaging within 28 days prior to first dosing in the study
• Subject must have received at least one prior line of chemotherapy for primary or secondary CNS lymphoma. There is no limit on the number of prior treatment regimens
• Absolute neutrophil count (ANC) >= 1 x 10^9/L
• Platelets >= 75 x 10^9/L
• Calculated creatinine clearance >= 30 mL/min using the Cockcroft Gault formula
• Bilirubin =< 1.5 x upper limit of normal (ULN). Subjects with Gilbert's syndrome may be enrolled despite a total bilirubin level > 1.5 mg/dL if their conjugated bilirubin is < 1.5 x ULN)
• Aspartate aminotransferase (AST) =< 2.5 x ULN
• Alanine aminotransferase (ALT) =< 2.5 x ULN
• International normalized ratio (INR) or prothrombin time (PT) and activated partial thromboplastin time (aPTT) =< 2 x ULN (in the absence of lupus anticoagulant)
• Subjects with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the treatment are eligible for this trial
• Female subjects of childbearing potential must have a negative serum pregnancy test within three days (72 hours) prior to initiating study treatment
• Female subjects of childbearing potential are women who are fertile following menarche and until becoming postmenopausal unless permanently sterile; permanent sterilization methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. Women are considered to be of non-reproductive potential if they meet any of the following criteria: * Postmenopausal, defined as at least 12 months with no menses without an alternative medical cause; in women <45 years of age a high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a post-menopausal state in women not using hormonal contraception or hormonal replacement therapy. In the absence of 12 months of amenorrhea, a single FSH measurement is insufficient * Have had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy or bilateral tubal ligation/occlusion, at least 6 weeks before Screening * Have a congenital or acquired condition that prevents childbearing
• Females of childbearing potential must be willing to abstain from heterosexual activity or to use 2 forms of effective methods of contraception from the time of informed consent until 2 days after the last dose of acalabrutinib. The two contraception methods can be comprised of two barrier methods, or a barrier method plus a hormonal method

Exclusion Criteria

• Prior cancer treatment that was completed less than 14 days prior to day 1 of study dosing or if subject has not recovered from all reversible acute toxic effects of the regimen to grade =< 1 or baseline
• Prior brain radiotherapy under the following conditions: * Whole-brain radiotherapy (WBRT) that was completed less than 28 days prior to day 1 of study dosing * Stereotactic radiosurgery (SRS) that was completed less than 14 days prior to day 1 of study dosing
• Currently receiving or has received an investigational agent within 28 days of first dosing with study treatment. Subjects should not currently be receiving investigational treatment or have received an investigational agent within 28 days of dosing
• Subject is pregnant or breastfeeding (Note: breast milk cannot be stored for future use while the mother is being treated on study)
• Subject has active CSF involvement that requires ongoing intrathecal chemotherapy
• Previous exposure to a BTK inhibitor
• Subjects with severe hepatic insufficiency, as defined by Child-Pugh score > 6
• Subject is receiving prohibited medications or treatments that cannot be discontinued/replaced by an alternative therapy. Subject requires treatment with a strong cytochrome P450 3A4 (CYP3A4) inhibitor/inducer. Subjects may be eligible if they are medically able to discontinue CYP3A4 inhibitors/inducers at least 14 days before the first dose of study treatment
• Subject requires or receiving anticoagulation with warfarin or equivalent vitamin K antagonists (e.g., phenprocoumon) within 14 days of first dose of study drug. Subjects requires or is taking direct oral anticoagulants (e.g. apixaban, rivaroxaban, edoxaban, Lovenox) within 7 days of first dose of study drug
• Subjects receiving capsule form of acalabrutinib may not be taking 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 and subjects receiving tablet form of acalabrutinib are eligible for enrollment to this study
• Subject is currently receiving any chemotherapy, anticancer immunotherapy. Note: Subjects receiving corticosteroids will be eligible, but corticosteroids are expected to be tapered off as soon as possible from a clinical standpoint
• Subject has clinically significant cardiovascular disease such as ventricular dysfunction, symptomatic coronary artery disease, uncontrolled or 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 (NYHA) Functional Classification at screening. Subjects with controlled, asymptomatic atrial fibrillation during screening can enroll on study
• Subject has familial short QT syndrome
• Subject has a history of malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel, symptomatic inflammatory bowel disease, partial or complete bowel obstruction, or gastric restrictions and bariatric surgery, such as gastric bypass that is likely to affect absorption
• Subject has a known history of infection with human immunodeficiency virus (HIV) or any uncontrolled active significant infection (e.g., bacterial, viral or fungal)
• Subject has a known history of drug-specific hypersensitivity or anaphylaxis to acalabrutinib (including active ingredient or excipient components)
• Subject has active bleeding or history of bleeding diathesis (e.g., hemophilia or von Willebrand disease)
• Subject has a history of uncontrolled AIHA (autoimmune hemolytic anemia) or ITP (idiopathic thrombocytopenic purpura)
• Subject has a history of significant cerebrovascular disease/event, including stroke or intracranial hemorrhage, within 6 months before the first dose of acalabrutinib
• Subject had major surgical procedure within 28 days of first dose of acalabrutinib. 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 acalabrutinib
• Subjects 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 deoxyribonucleic acid (DNA) polymerase chain reaction (PCR) testing during the study. Subjects who are core antibody positive and viral load negative must receive entecavir prophylaxis. Those who are HbsAg-positive or hepatitis B PCR positive will be excluded
• Subjects who are hepatitis C antibody positive must have a negative polymerase chain reaction (PCR) result. Those who are hepatitis C PCR positive will be excluded
• 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
• History of or ongoing confirmed progressive multifocal leukoencephalopathy (PML)
• Received a live virus vaccination within 28 days of first dose of study drug
• Any active significant infection (e.g., bacterial, viral or fungal, including subjects with positive cytomegalovirus [CMV] DNA polymerase chain reaction [PCR])
• Concurrent participation in another therapeutic clinical trial
• Current life-threatening illness, medical condition, or organ system dysfunction which, in the Investigator’s opinion, could compromise the subject’s safety or put the study at risk