A Pilot Study of Acalabrutinib in Relapsed/Refractory Primary and Secondary CNS Lymphomas

  • End date
    Dec 8, 2028
  • participants needed
  • sponsor
    UNC Lineberger Comprehensive Cancer Center
Updated on 8 April 2022
neutrophil count
chemotherapy regimen
mantle cell lymphoma
anticancer agents


The purpose of this study is to test whether giving acalabrutinib is safe and effective in controlling relapsed central nervous system (CNS) lymphoma. Currently, there are no FDA-approved treatments for relapsed CNS lymphoma. Although acalabrutinib has not been approved for the treatment of CNS lymphoma, it was approved for the treatment of another type of lymphoma (mantle cell), by the Food and Drug Administration (FDA).

Acalabrutinib acts similar to another cancer drug called ibrutinib. lbrutinib was tested in several research trials for the management of CNS lymphomas, and the results were promising. Acalabrutinib and ibrutinib attack a similar target found in CNS lymphoma. Acalabrutinib may do a better job in attacking this target than ibrutinib. The study doctors will be looking to see if acalabrutinib can shrink cancer cells.

The participants will be given acalabrutinib and isavuconazole, because isavuconazole helps in preventing fungal infections that may occur during acalabrutinib treatment.


This multicenter open-label, single-arm, pilot study explores a safe and effective treatment for relapsed central nervous system lymphoma. The study investigates the antitumor effects and safety of acalabrutinib in subjects with relapsed primary central nervous system lymphoma (PCNSL) or relapsed secondary CNS lymphoma (SCNSL) with no evidence of current systemic disease. Types of SCNSL included in the study are: Diffuse large B-cell lymphoma, mantle cell lymphoma, plasmablastic lymphoma, and lymphoplasmacytic lymphoma. Up to 16 subjects will be enrolled to attain a total of 15 evaluable subjects.

Duration of Therapy: Treatment with acalabrutinib and isavuconazole will continue unless

  • Disease progression
  • Inter-current illness that prevents further administration of treatment
  • Unacceptable adverse event(s)
  • Pregnancy
  • Subject decides to withdraw from study treatment,
  • General or specific changes in the subject's condition render the subject unacceptable for further treatment in the judgment of the investigator, or
  • Subject is lost to follow up

Duration of Follow-up All subjects will be followed for survival for 5 years or until death, whichever occurs first.

Condition Central Nervous System Lymphoma
Treatment acalabrutinib, Isavuconazole
Clinical Study IdentifierNCT04548648
SponsorUNC Lineberger Comprehensive Cancer Center
Last Modified on8 April 2022


Yes No Not Sure

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 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 adequate performance status as defined by The Eastern Cooperative Oncology Group (ECOG) of ≤ 2. (Note: Performance status can be assessed after administration of corticosteroids.)
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
Subject is able to receive isavuconazole for prophylaxis of invasive aspergillosis while subject receives acalabrutinib therapy
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)
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
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
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 brain radiotherapy under the following conditions
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
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
Currently participating in or has participated in a study of an investigational
agent within 28 days of first dosing with study treatment
Subject is pregnant or breastfeeding. 5. Subject has active cerebrospinal fluid
(CSF) involvement that requires ongoing intrathecal chemotherapy
Previous exposure to a Bruton Tyrosine Kinase (BTK) inhibitor. 7. Subjects with
Subject requires or receiving anticoagulation with warfarin or equivalent vitamin K
severe hepatic insufficiency, as defined by Child-Pugh Score > 6
antagonists within 14 days of first dose of study drug. Subjects requires or is taking
Subject is receiving prohibited medications or treatments as listed in the protocol
direct oral anticoagulants within 7 days of first dose of study drug
that cannot be discontinued/replaced by an alternative therapy
Subject is currently receiving any chemotherapy, anticancer immunotherapy. 12
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
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
Subject has familial short QT syndrome. 14. Subject has a history of malabsorption
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
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 HIV or any uncontrolled active
Subject has active bleeding or history of bleeding diathesis. 18. Subject has a
significant infection
Subject has a known history of drug-specific hypersensitivity or anaphylaxis to
acalabrutinib or isavuconazole
history of uncontrolled autoimmune hemolytic anemia (AIHA) or idiopathic
thrombocytopenic purpura (ITP)
Subject has a history of significant cerebrovascular disease/event, including
stroke or intracranial hemorrhage, within 6 months before the first dose of
Subject had major surgical procedure within 28 days of first dose of
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
Subjects who are hepatitis C antibody positive must have a negative polymerase
History of or ongoing confirmed progressive multifocal leukoencephalopathy (PML)
chain reaction (PCR) result. Those who are hepatitis C PCR positive will be excluded
Received a live virus vaccination within 28 days of first dose of study drug
Subjects with evidence of disease that investigator decides that is not suitable
Any active significant infection. 27. Concurrent participation in another
to enroll in the study
therapeutic clinical trial. 28. 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
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