Clinical trial NCT05117814: Zanubrutinib Monotherapy in Relapsed/Refractory Central Nervous System Lymphoma
Official title: Zanubrutinib Monotherapy in Relapsed/Refractory Central Nervous System Lymphoma
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: CNS Lymphoma
Keywords: CNSL
Lead sponsor: Peking University People's Hospital
Sponsor class: OTHER
First posted: 2021-11-11
Enrollment: 20
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: Inclusion Criteria:

Key inclusion criteria:

1. Able to understand and willing to sign a written informed consent document
2. Men and woman at least 18 years of age on the day of consenting to the study
3. Histologically documented DLBCL.
4. Relapsed/refractory PCNSL or relapsed/refractory SCNSL
5. 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.
6. An ECOG performance status≤2
7. 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:

1. Patients with SCNSL actively receiving treatment for extra-CNS disease
2. Concurrently using other approved or investigational antineoplastic agents
3. Prior chemotherapy, targeted therapy, or radiation therapy within 4 weeks
4. Prior exposure to a BTK inhibitor
5. Concurrently using more than 8mg of dexamethasone daily or the equivalent
6. History of other active malignancies within 2 years of study entry
7. Major surgery within 4 weeks of screening or not recovered from the side effects of such surgery
8. Known to have human immunodeficiency virus (HIV) infection
9. 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
10. Active infection systemic including infections requiring oral or intravenous antimicrobials
11. Currently active clinically significant cardiovascular disease
12. QTcF \> 480 msecs or other significant electrocardiogram (ECG) abnormalities
13. Unable to swallow capsules or disease significantly affecting gastrointestinal function
14. 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
15. Required ongoing treatment with medication that are strong cytochrome P450, family 3, subfamily A (CYP3A) inhibitors or strong CYP3A inducers
16. History of stroke or intracranial hemorrhage within 6 months prior to enrollment
17. Inability to comply with study procedures
18. Pregnant or lactating women
19. Prior allogenic hematopoietic stem cell transplantation (autologous stem cell transplant is NOT an exclusion)

Primary outcomes:
measure: Overall response rate (ORR)
timeFrame: 2 years
Secondary outcomes:
measure: Time to response (TTR)
timeFrame: 2 years
measure: Duration of response (DOR)
timeFrame: 2 years
measure: The concentration of zanunbrutinib in CSF and plasma
timeFrame: 2 months
measure: Progression-free survival (PFS)
timeFrame: 2 years
measure: Treatment-related adverse events (TRAE)
timeFrame: During zanubrutinib treatment until 30+/-7 days after discontinuation.
Other outcomes:
measure: Overall survival (OS)
timeFrame: 4 years
measure: ctDNA
timeFrame: 2 years
Locations:
city: Beijing
country: China
facility: Peking University People's Hospital
state: Beijing
Study officials:
affiliation: Peking University Peoples' Hospital
name: Shenmiao Yang, MD
role: PRINCIPAL_INVESTIGATOR
References: