Inclusion Criteria:
1. Willing and able to participate in all required evaluations and procedures in this
study protocol, including swallowing capsules and tablets without difficulty.
2. 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).
3. Age ≥18 years at the time of consent.
4. Subject has adequate performance status as defined by The Eastern Cooperative Oncology
Group (ECOG) of ≤ 2. (Note: Performance status can be assessed after administration of
corticosteroids.)
5. 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.
6. Subject has B-cell Non-Hodgkin Lymphoma.
7. 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.
8. 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.
9. Subject has adequate organ function as demonstrated by: System Laboratory Value
Hematological* Absolute Neutrophil Count (ANC) ≥ 1 x 109/L Platelets ≥ 75 x 109/L
Renal* Calculated creatinine clearance ≥ 30 mL/min using the Cockcroft-Gault formula
(Appendix B) Hepatic* Bilirubin ≤ 1.5 × 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× ULN) Aspartate aminotransferase (AST) ≤ 2.5 × ULN
Alanine aminotransferase (ALT) ≤ 2.5 × ULN Coagulation International Normalized Ratio
(INR) or Prothrombin Time (PT) and Activated Partial Thromboplastin Time (aPTT) ≤ 2 ×
ULN (in the absence of lupus anticoagulant)
10. Subject is able to receive isavuconazole for prophylaxis of invasive aspergillosis
while subject receives acalabrutinib therapy.
11. 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
investigational regimen are eligible for this trial.
12. Female subjects of childbearing potential must have a negative serum pregnancy test
within three days (72 hours) prior to initiating study treatment. Note: Females are
considered of childbearing potential unless they are surgically sterile (have
undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or they
are naturally postmenopausal for at least 12 consecutive months. Documentation of
postmenopausal status must be provided.
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:
1. Subjects meeting any of the following exclusion criteria will not be able to participate
in this study 2.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.
3. 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 competed less than 14 days prior to Day 1 of
study dosing.
3. Currently participating in or has participated in a study of an investigational
agent within 28 days of first dosing with study treatment.
4. 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.
5.Subject is pregnant or breastfeeding. 6. Subject has active cerebrospinal fluid
(CSF) involvement that requires ongoing intrathecal chemotherapy.
7. Previous exposure to a Bruton Tyrosine Kinase (BTK) inhibitor. 8. Subjects with
severe hepatic insufficiency, as defined by Child-Pugh Score > 6.
9. Subject is receiving prohibited medications or treatments as listed in the protocol
that cannot be discontinued/replaced by an alternative therapy.
10. Subject requires or receiving anticoagulation with warfarin or equivalent vitamin
K antagonists within 14 days of first dose of study drug. Subjects requires or is
taking direct oral anticoagulants within 7 days of first dose of study drug.
11. Subject requires treatment with proton pump inhibitors. Subjects receiving proton
pump inhibitors who switch to H2-receptor antagonists or antacids are eligible for
enrollment to this study.
12. Subject is currently receiving any chemotherapy, anticancer immunotherapy. 13.
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.
14. Subject has familial short QT syndrome. 15. 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.
16. Subject has a known history of infection with HIV or any uncontrolled active
significant infection.
17. Subject has a known history of drug-specific hypersensitivity or anaphylaxis to
acalabrutinib or isavuconazole.
18. Subject has active bleeding or history of bleeding diathesis. 19. Subject has a
history of uncontrolled autoimmune hemolytic anemia (AIHA) or idiopathic
thrombocytopenic purpura (ITP).
20. Subject has a history of significant cerebrovascular disease/event, including
stroke or intracranial hemorrhage, within 6 months before the first dose of
acalabrutinib.
21. Subject had major surgical procedure within 28 days of first dose of
acalabrutinib.
22. Subject 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.
Subjects who are core antibody positive and viral load negative must receive entecavir
Those who are HbsAg-positive, or hepatitis B PCR positive will be excluded.
23. 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.
24. Subjects with evidence of disease that investigator decides that is not suitable
to enroll in the study.
25. History of or ongoing confirmed progressive multifocal leukoencephalopathy (PML).
26. Received a live virus vaccination within 28 days of first dose of study drug.
27. Any active significant infection. 28. Concurrent participation in another
therapeutic clinical trial. 29. 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.
