Zanubrutinib Monotherapy in Relapsed/Refractory Central Nervous System Lymphoma

Study Overview
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Brief Summary
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Zanubrutinib is a novel BTK inhibitor with proven activity in patients with various B-cell lymphomas addicted to the B-cell receptor signaling pathway.

Detailed Description
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Studies involving gene expression profiling and next generation sequencing have demonstrated that CNS lymphomas mostly are of the ABC-subtype and harbor mutations that reinforce BCR signaling. Ibrutinib, as the first BTK inhibitor, showed substantial activity in patients with R/R PCNSL and R/R SCNSL. Zanubrutinib is a novel BTK inhibitor with proven activity in patients with various B-cell lymphomas addicted to the B-cell receptor signaling pathway. In addition, pharmacological studies demonstrated the free drug exposure of zanubrutinib at 160 mg BID is roughly 10 times that of ibrutinib at 560 mg QD, and penetration into the CNS by zanubrutinib and ibrutinib is similar, suggesting the potential activity of zanubrutinib in the treatment of CNS lymphomas. However, the outcome of R/R PCNSL and R/R SCNSL patients treated with zanubrutinib monotherapy is still unclear.

Official Title
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Zanubrutinib Monotherapy in Relapsed/Refractory Central Nervous System Lymphoma

Conditions
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CNS Lymphoma

Intervention / Treatment
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* Drug: Zanubrutinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Key inclusion criteria: Able to understand and willing to sign a written informed consent document Men and woman at least 18 years of age on the day of consenting to the study Histologically documented DLBCL. Relapsed/refractory PCNSL or relapsed/refractory SCNSL Patients with parenchymal lesions must have unequivocal evidence of disease progression on imaging (MRI or the brain or head CT) prior to study enrollment. For patients with leptomeningeal disease only, CSF cytology must document lymphoma cells and/or imaging findings consistent with CSF disease prior to study enrollment. An ECOG performance status≤2 Adequate bone marrow and organ function shown by: (1) Neutrophils ≥ 0.75 x 109/L independent of growth factor support within 7 days of study entry (2) Platelets ≥ 50 x 109/L independent of growth factor support or transfusion within 7 days of study entry (3) Creatinine clearance of ≥ 30 mL/min (4) Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 x upper limit of normal (ULN) (5) Bilirubin ≤ 1.5 x ULN (6) International normalized ratio ≤ 1.5 and activated partial thromboplastin time ≤ 1.5 x ULN. 8. Recovered to grade 1 toxicity from prior therapy before the first dose of study drug 9. Agree to use highly effective methods of birth control during the period of therapy and for 3 months after the last dose of the study drug. Exclusion Criteria: Patients with SCNSL actively receiving treatment for extra-CNS disease Concurrently using other approved or investigational antineoplastic agents Prior chemotherapy, targeted therapy, or radiation therapy within 4 weeks Prior exposure to a BTK inhibitor Concurrently using more than 8mg of dexamethasone daily or the equivalent History of other active malignancies within 2 years of study entry Major surgery within 4 weeks of screening or not recovered from the side effects of such surgery Known to have human immunodeficiency virus (HIV) infection Known to have a history of active or chronic infection with hepatitis C virus (HCV) or hepatitis B virus (HBV) as determined by serologic tests Active infection systemic including infections requiring oral or intravenous antimicrobials Currently active clinically significant cardiovascular disease QTcF > 480 msecs or other significant electrocardiogram (ECG) abnormalities Unable to swallow capsules or disease significantly affecting gastrointestinal function Any life-threatening illness, medical condition or organ system dysfunction which, in the investigator's opinion, could have compromised the patient's safety, or put the study at risk Required ongoing treatment with medication that are strong cytochrome P450, family 3, subfamily A (CYP3A) inhibitors or strong CYP3A inducers History of stroke or intracranial hemorrhage within 6 months prior to enrollment Inability to comply with study procedures Pregnant or lactating women Prior allogenic hematopoietic stem cell transplantation (autologous stem cell transplant is NOT an exclusion)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Zanubrtuinib<br>Zanubrutinib 320mg Qd | Drug: Zanubrutinib<br>* as long as 24 months or consolidated with ASCT or WBRT after achieving PR or CR<br>* Other names: BRUKINSA®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall response rate (ORR) | Based on the Investigator assessed CR and PR, with the enhanced CT scan, the cerebrospinal fluid (CSF) examination, and the ophthalmological examination. | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to response (TTR) | Time from the first dose of zanubrutinib to the first assessment of >=PR | 2 years | 
| Duration of response (DOR) | Time from the first assessment of >=PR to symptom, CT scan, and/ or CSF confirmed progressive disease (PD) | 2 years | 
| The concentration of zanunbrutinib in CSF and plasma | The concentration of zanunbrutinib in CSF and plasma 2 hours after taking the drug | 2 months | 
| Progression-free survival (PFS) | The time from the first dose to PD or death whichever occurs earlier. | 2 years | 
| Treatment-related adverse events (TRAE) | Adverse events during zanubrutinib treatment. | During zanubrutinib treatment until 30+/-7 days after discontinuation. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CNSL