Zanubrutinib Plus BR in Newly Diagnosed Symptomatic WM

Study Overview
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Brief Summary
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This study aims to evaluate the long-term efficacy of BTK inhibitor Zanubrutinib combined bendamustine and rituximab (ZBR) for time-limited treatment of Waldenstrom macroglobulinemia, The combination therapy is expected to improve the remission depth, prolong the remission time, and improve the progression-free survival and overall survival of newly diagnosed WM patients. On the one hand, the patients have to bear a long-term economic burden, which is often difficult for some patients to adhere to for a long time. On the other hand, in the course of long-term treatment of BTKi, drug resistance and intolerable side effects are prone to occur. At the same time, it can prevent the disease rebound after the withdrawal of BTKi, so as to achieve the phased withdrawal of WM

Detailed Description
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WM not only has the characteristics of lymphoma, such as lymphadenopathy, hepatosplenomegaly, and tumor cells expressing CD20, but also has the characteristics of myeloma, such as secreting monoclonal IgM, and tumor cells expressing plasma cell differentiation marker CD38, etc. Clinical studies have also shown that BR regimen and BTK inhibitor zanubrutinib are effective for WM. This study aims to evaluate the long-term efficacy of BTK inhibitor Zanubrutinib combined bendamustine and rituximab (ZBR) for time-limited treatment of Waldenstrom macroglobulinemia, The combination therapy is expected to improve the remission depth, prolong the remission time, and improve the progression-free survival and overall survival of newly diagnosed WM patients. On the one hand, the patients have to bear a long-term economic burden, which is often difficult for some patients to adhere to for a long time. On the other hand, in the course of long-term treatment of BTKi, drug resistance and intolerable side effects are prone to occur. At the same time, it can prevent the disease rebound after the withdrawal of BTKi, so as to achieve the phased withdrawal of WM. This prospective phase II study was designed to evaluate the rate of deep response in newly diagnosed symptomatic WM. Eligible patients received ZBR for 6 cycles followed by zanubrutinib monotherapy for an additional 6 months.

Official Title
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Phase II Clinical Study of Zanubrutinib Combined With Bendamustine and Rituximab (ZBR) for Time-limited Treatment of Waldenstrom Macroglobulinemia

Conditions
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Waldenstrom Macroglobulinemia

Intervention / Treatment
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* Drug: Zanubrutinib, Bendamustine and Rituximab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: The gender of the patient is not limited, and the age is ≥18 years old; Must meet WM's diagnostic standards; The patient is an untreated or patient who has not undergone standard treatment. The specific conditions are as follows: No combined chemotherapy with BTKi, BR, RCD, VRD, CHOP and COP No treatment regimen containing fludarabine Chlorambucil or cyclophosphamide for less than 4 weeks (alone or in combination with adrenal glucocorticoids) The above treatment did not reach the treatment response (MR) If the above treatment has been applied, the treatment needs to be stopped for 2 weeks before entering the group to start treatment The indications for the treatment of indolent lymphoma mainly include (at least one of the following conditions): Symptomatic hyperviscosity; Symptomatic peripheral neuropathy; Amyloidosis; Cold agglutinin disease; cryoglobulinemia; Disease-related cytopenia (Hb<100 g/L, PLT<100×10^9/L); Giant lymph nodes; Those with systemic systemic symptoms: for two weeks/recurrent fever (above 38℃) and not caused by infection, or Night sweats and/or weight loss >10% within 6 months; The disease progresses rapidly, for example, the lymph nodes increase by more than 50% within 2 months, and/or peripheral blood lymphocytes absolute value doubling time <6 months, and/or rapid hemoglobin or platelet non-autoimmune causes slow down When there is evidence that the disease has transformed. ECOG score ≤ 2 points Laboratory examination: neutrophils ≥ 0.75×10^9/L; platelets ≥ 50×10^9/L; total bilirubin ≤ 2.5 times upper limit; alanine aminotransferase/aspartate aminotransferase ≤3 times upper limit. Creatinine clearance rate ≥ 30ml/min. The patient's expected survival time is ≥ 3 months. Exclusion Criteria: Malignant tumors (including active central nervous system lymphoma) other than B-NHL have been diagnosed or treated within the past year; There is clinical evidence that large cell lymphoma transformation has occurred; Non-lymphoma-related liver and kidney damage: alanine aminotransferase (ALT)> 3 times the upper limit of normal value, aspartate aminotransferase (AST)> 3 times the upper limit of normal value, total bilirubin (TBIL)> upper limit of normal value 2 Times, serum creatinine clearance rate <30ml/min; Other serious medical conditions will affect the study (such as uncontrolled diabetes, gastric ulcers, other serious cardiopulmonary diseases, etc.). The decision-making power belongs to the researcher; Known history of infection with human immunodeficiency virus (HIV) or active hepatitis B virus (HBV) infection, or any uncontrolled active systemic infection requiring intravenous antibiotics. Central nervous system dysfunction with clinical manifestations or central invasion (Bing-Neel syndrome); Patients who have undergone major surgery (not including lymph node biopsy) within the past 14 days or expected major surgery during treatment; Inability to swallow capsules or suffer from malabsorption syndrome, diseases that significantly affect gastrointestinal function, have undergone gastric or small bowel resection, symptomatic inflammatory bowel disease or ulcerative colitis, partial or complete intestinal obstruction. Need to receive strong cytochrome P450 (CYP) 3A inhibitor treatment. Women who are pregnant or breastfeeding, women of childbearing age who have not taken contraception; Allergy to the drugs used.

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
Interventional Model Description: Patients were treated with ZBR regimen for 6 cycles, followed by Zanubrutinib monotherapy for 6 months.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Zanubrutinib, bendamustine, rituximab combination therapy Group<br>Patients were treated with ZBR regimen for 6 cycles, followed by zanubrutinib monotherapy for an additional 6 months. | Drug: Zanubrutinib, Bendamustine and Rituximab<br>* Zanubrutinib, 160mg orally, twice a day; Bendamustine 70 mg/m2 on days 1 and 2 of each cycle; Rituximab (375 mg/m2 intravenously on day 0 of each cycle. ZBR was administered every 4 weeks for a total of 6 cycles, followed by maintenance therapy with zanubrutinib monotherapy for another 6 months.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Best combined complete response (CR) and very good partial response (VGPR) | To evaluate the efficacy of zanubrutinib plus bendamustine and rituximab (ZBR) regimen in the treatment of newly diagnosed WM patients, mainly the best deep response rate, namely the best deep response rate (VGPR and above). | up to the end of 12 cycles of treatment(each cycle is 28 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall objective response rate (ORR), complete response rate(CR),major response rate(MR) | using criteria from 6th international workshop on WM | up to the end of 12 cycles of treatment(each cycle is 28 days) | 
| Time to response, time to best response | Defined as after initiation of treatment， the time interval between the first documented remission of disease | up to the end of 12 cycles of treatment(each cycle is 28 days) | 
| Overall survival(OS) | 3-year OS rate after treatment | Up to 3 years after the end of treatment | 
| Progression free survival(PFS) | 3-year PFS rate after treatment | Up to 3 years after the end of treatment | 
| Duration of Response | DOR is defined as the time from the first occurrence of overall response (CR, PR or MR) until disease progression or death due to any cause. | Up to 3 years after the end of treatment | 
| Time to Next Treatment | Defined as the amount of time from the start of trial until the patient requires a new form of treatment to treat their WM | Up to 3 years after the end of treatment | 
| Safety of treatment regimens | Defined as treatment-related toxicity | Up to 3 years after the end of treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Waldenstrom macroglobulinemia, Zanubrutinib, newly diagnosed