LCCC1841: A Phase 2 Trial of Acalabrutinib in Relapsed/Refractory Primary and Secondary CNS Lymphomas

  • STATUS
    Recruiting
  • End date
    Dec 23, 2028
  • participants needed
    32
  • sponsor
    UNC Lineberger Comprehensive Cancer Center
Updated on 23 July 2021
cancer
corticosteroids
lymphoma
neutrophil count
chemotherapy regimen
mantle cell lymphoma
ibrutinib
anticancer agents

Summary

The purpose of this study is to see if acalabrutinib is effective in treating a type of cancer call central nervous system (CNS) lymphoma. Acalabrutinib has not been approved by the Food and Drug Administration (FDA) for the treatment of CNS lymphoma. However, FDA has approved its use for treatment of another type of lymphoma called mantle cell lymphoma. Currently, there are no standard FDA approved treatments for treatment of CNS lymphoma.

Acalabrutinib acts similar to another cancer drug called ibrutinib. Ibrutinib was tested in several research trials for management of CNS lymphomas, and the results were promising. Acalabrutinib and ibrutinib attack a similar target found in CNC lymphoma. Research studies show that acalabrutinib does a better job in attacking this target than ibrutinib, and this might be beneficial for using this drug in treating CNS lymphoma. The purpose of this study is test whether giving acalabrutinib is safe and could help controlling with CNS lymphoma. The study doctors will be looking to see if acalabrutinib can shrink the cancer.

In this research study, participants will be given acalabrutinib and isavuconazol, because it helps in preventing fungal infections. Fungal infection is a common side effect of acalabrutinib. Treatment with acalabrutinib and isavuconazole will continue unless the cancer progresses or participants experience bad side effects.

Description

LCCC 1841 is a multicenter open-label, single-arm, phase 2 study designed to investigate the antitumor effects of acalabrutinib in subjects with relapsed primary central nervous system lymphoma (PCNSL), and relapsed secondary CNS lymphoma (SCNSL) with no evidence of current systemic disease. Subjects with the following histological subtypes of lymphoma will be included in the study: diffuse large B-cell lymphoma (DLBCL, all subtypes); mantle cell lymphoma (MCL, all subtypes); plasmablastic lymphoma, and lymphoplasmacytic lymphoma. Up to 32 subjects will receive acalabrutinib at the dose of 100 mg approximately every 12 hours. A Simon two-stage design will be used to minimize the expected sample size if the regimen has low activity. In the first stage, 15 evaluable subjects will be enrolled and treated. If =8 subjects have an overall response of stable disease or better as determined by the International Primary CNS Lymphoma Collaborative Group Response Assessment Criteria , an additional 13 subjects will be enrolled and treated in the second stage of the study for a total of 28 evaluable subjects treated on the trial. The study will accrue up to 32 subjects to ensure data from 28 evaluable subjects. If <8 subjects have an overall response of stable disease or better as determined by the International Primary CNS Lymphoma Collaborative Group Response Assessment Criteria, the study will be closed to accrual and no additional subjects will be enrolled. If the study shows a positive effect of acalabrutinib in treating CNS lymphomas, acalabrutinib could become the standard relapsed CNS lymphoma regimen, not only for PCNSL, but also in certain subtypes of SCNSL. Any complete responses to acalabrutinib treatment will be clinically notable as spontaneous remissions do not occur.

In a previous study, ibrutinib showed a CR rate of 45% and an ORR of 68% ; in another study ], ibrutinib showed a CR rate of 17% and an ORR of 55%. Thus, in order to recommend further investigation of acalabrutinib as a regimen for primary CNS lymphoma, acalabrutinib treatment must show an overall response rate (ORR) of at least 70%, which would demonstrate that it is not inferior to previously approved regimens.

Details
Condition Lymphoma, Lymphoproliferative Disorder, Lymphoma, lymphomas
Treatment acalabrutinib, Isavuconazole
Clinical Study IdentifierNCT04548648
SponsorUNC Lineberger Comprehensive Cancer Center
Last Modified on23 July 2021

Eligibility

Yes No Not Sure

Inclusion Criteria

Written informed consent obtained to participate in the study and HIPAA authorization for release of personal health information
Age 18 years at the time of consent
Subject has adequate performance status as defined by 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
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)
Subject is able to receive isavuconazole for prophylaxis of invasive aspergillosis while subject receives acalabrutinib therapy
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

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
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
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 (Note: breast milk cannot be stored for
future use while the mother is being treated on study)
Subject has a known additional malignancy that is active and/or progressive
requiring treatment; exceptions include basal cell or squamous cell skin
cancer, in situ cervical or bladder cancer, or other cancer for which the
subject has been disease-free for at least five years
\. Subject has active CSF involvement that requires ongoing intrathecal
chemotherapy
\. Previous exposure to a BTK inhibitor. 8. Subjects with severe hepatic
insufficiency, as defined by Child-Pugh Score > 6 (Appendix C)
\. Subject is receiving prohibited medications or treatments as listed in
Section 5.3 of the protocol that cannot be discontinued/replaced by an
alternative therapy. Subject requires treatment with a strong cytochrome P450
A4 (CYP3A4) inhibitor/inducer other than isavuconazole (please consult
Section 5.3). 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
\. Subject requires treatment with 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 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 (Appendix
D) at screening. Subjects with controlled, asymptomatic atrial fibrillation
during screening can enroll on study
\. 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
\. Subject has a known history of infection with 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 or isavuconazole (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
\. Subject must either have hepatitis B core antibody negative OR if a
subject is hepatitis B core antibody positive they must have their hepatitis B
viral load checked. These subjects will be excluded if their viral load is
positive. Subject who are core antibody positive and viral load negative will
be considered eligible, but must receive entecavir prophylaxis
\. 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
\. Subjects who are unable to swallow oral medications
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