R-MTX-zanbrutinib in Secondary CNS Lymphoma

Study Overview
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Brief Summary
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Secondary central nervous system lymphoma (SCNSL) occurred in about 5% of patients with diffuse large B-cell lymphoma (DLBCL). The prognosis of SCNSL is very poor. A number of retrospective studies have shown that the median overall survival (mOS) since the diagnosis of CNSL is only 2.5-3.5 months, and the 2-year OS rate is only 20%. At present, there is no consensus on the treatment of SCNSL, and new therapeutic strategies are urgently needed. Zanubrutinib is a new second-generation BTK inhibitor, which has showed good efficacy and safety in a variety of B-NHL. Zanubrutinib has showed good blood-brain barrier permeability in preclinical studies. This study attempts to evaluate the efficacy and safety of zanubrutinib combined with rituximab and high-dose methotrexate in the treatment of SCNSL in patients with DLBCL.

Official Title
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Phase II Study of Zanubrutinib in Combination With Rituximab and Methotrexate, Followed by Zanubrutinib Maintenance in Patients With Secondary Central Nervous System Lymphoma (SCNSL)

Conditions
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Secondary Central Nervous System Lymphoma

Intervention / Treatment
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* Drug: Zanubrutinib, high-dose methotrexate (HD-MTX), rituximab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men and women ≥ 18, and ≤75 years of age Histologically documented systemic diffuse large B-cell lymphoma(DLBCL) Central nervous system (CNS) relapse (meningeal or /and intraparenchymal) with or without systemic lymphoma manifestations All patients need to have received at least one and ≤4 lines of prior therapy systemic lymphoma directed therapy. ECOG performance score 0-3 Participants must have adequate bone marrow and organ function shown by: Absolute neutrophil count (ANC) ≥ 1.5 x 109/L, Hemoglobin (Hgb) ≥ 9 g/dL, Platelets ≥ 75 x 109/L(≥ 50 x 109/L if bone marrow involvement) Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 times the upper limit of normal, total bilirubin ≤ 2 times the upper limit of normal International Normalized Ratio (INR) ≤ 1.5 and PTT (aPTT) ≤ 1.5 times the upper limit of normal serum creatinine (mg/dL)) ≤ 1.5 times the upper limit of normal ; calculated creatinine clearance(CrCl) ≥ 40ml/min using the Cockcroft-Gault equation Expected survival greater than 3 months Did not receive targeting agents within 10 days or receive chemortherapy, radiotherapy, or monoclonal antibody within 3 weeks Woman of reproductive potential must agree to use highly effective methods of birth control during the period of therapy and for 30 days after the last dose of the study drug. Men who are sexually active must agree to use highly effective contraception during the period of therapy and for 3 months after the last dose Ability of participants or Legally Authorized Representative (LAR) to understand and the willingness to sign a written informed consent document Exclusion Criteria: Newly diagnosed DLBCL with CNS involvement Previous treatment with Bruton's Tyrosine Kinase (BTK) inhibitors Received targeting agents within 10 days or received chemortherapy, radiotherapy, or monoclonal antibody within 3 weeks Patient has significant abnormalities on screening electrocardiogram (EKG) and active and significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, hypertension, valvular disease, pericarditis, or myocardial infarction within 6 months of screening History of severe bleeding diseases Patient is using warfarin or any other Coumadin-derivative anticoagulant or vitamin K antagonists. Patients must be off warfarin-derivative anticoagulants for at least seven days prior to starting the study drug. Low molecular weight heparin is allowed. Patients with congenital bleeding diathesis are excluded Patient is taking a drug known to be a moderate and strong inhibitor or inducers of the P450 isoenzyme CYP3A. Participants must be off P450/CYP3A inhibitors and inducers for at least two weeks prior to starting the study drug Patient is known to have human immunodeficiency virus (HIV) infection Patient is 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 Patient is known to have an uncontrolled active systemic infection Patients with serous cavity effustion Patient underwent major systemic surgery ≤ 4 weeks prior to starting the trial treatment or who has not recovered from the side effects of such surgery Women who are pregnant or nursing (lactating) The patient is unwell or unable to participate in all required study evaluations and procedures

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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: Experimental arm: Zanubrutinib, high-dose methotrexate (HD-MTX), rituximab<br>Zanubrutinib in combination with rituximab and methotrexate, followed by zanubrutinib maintenance in patients with secondary central nervous system lymphoma (SCNSL) | Drug: Zanubrutinib, high-dose methotrexate (HD-MTX), rituximab<br>* Induction therapy: Zanubrutinib will be given as 160mg bid orally between days 1 and 14 of each 14-day cycle; rituximab will be given at 375mg/m2 intravenously on day 1 of each cycle; methotrexate at 3.5g/m2 for patients ≤65 or 1.5g/m2 for patients >65 (standard hydration/leucovorin support) will be given intravenously on day 2 of each 14-day cycle; for 6 cycles. Consolidation therapy: For patients ≤65, autologous hematopoietic stem cell transplantation (ASCT with a conditioning regimen of thiotepa/carmustine) will be given as consolidation treatment after induction therapy. Maintenance therapy:Drug: zanubrutinib. Zanubrutinib will be given as 160mg bid orally continuously until progression of the disease (PD), intolerable toxicity, death, or patient/investigator discretion.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| progression free survival | Progression-free survival (PFS) is defined as the time from the date of treatment start to the date of the first documented PD or death due to any cause | 1-year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall response rate (ORR) |  | at the end of 6 cycles of induction therapy (each cycle is 14 days) | 
| Complete response (CR) |  | at the end of 6 cycles of induction therapy | 
| Partial response (PR) |  | at the end of 6 cycles of induction therapy (each cycle is 14 days) | 
| Overall survival (OS) |  | 1-year | 
| safety/tolerability by assessing the frequency and severity of adverse events |  | at the end of 6 cycles of induction therapy (each cycle is 14 days), 1 year and 2 year maintenance therapy |