ZBR: Zanubrutinib Plus BR in Newly Diagnosed Symptomatic WM

Sponsor

Institute of Hematology & Blood Diseases Hospital (Other)

Overall Status

Recruiting

CT.gov ID

NCT05914662

Collaborator

(none)

Enrollment

Location

Arm

Anticipated Duration (Months)

0.9

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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

Condition or Disease	Intervention/Treatment	Phase
Waldenstrom Macroglobulinemia	Drug: Zanubrutinib, Bendamustine and Rituximab	Phase 2

Detailed Description

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

30 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Intervention Model Description:

Patients were treated with ZBR regimen for 6 cycles, followed by Zanubrutinib monotherapy for 6 months.Patients were treated with ZBR regimen for 6 cycles, followed by Zanubrutinib monotherapy for 6 months.

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Feb 15, 2023

Anticipated Primary Completion Date :

Mar 15, 2025

Anticipated Study Completion Date :

Dec 15, 2025

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Zanubrutinib, bendamustine, rituximab combination therapy Group Patients were treated with ZBR regimen for 6 cycles, followed by zanubrutinib monotherapy for an additional 6 months.	Drug: Zanubrutinib, Bendamustine and Rituximab 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.

Arm

Intervention/Treatment

Experimental: Zanubrutinib, bendamustine, rituximab combination therapy Group

Patients were treated with ZBR regimen for 6 cycles, followed by zanubrutinib monotherapy for an additional 6 months.

Drug: Zanubrutinib, Bendamustine and Rituximab

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.

Outcome Measures

Primary Outcome Measures

Best combined complete response (CR) and very good partial response (VGPR) [up to the end of 12 cycles of treatment(each cycle is 28 days)]
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).

Secondary Outcome Measures

Overall objective response rate (ORR), complete response rate(CR),major response rate(MR) [up to the end of 12 cycles of treatment(each cycle is 28 days)]
using criteria from 6th international workshop on WM
Time to response, time to best response [up to the end of 12 cycles of treatment(each cycle is 28 days)]
Defined as after initiation of treatment， the time interval between the first documented remission of disease
Overall survival(OS) [Up to 3 years after the end of treatment]
3-year OS rate after treatment
Progression free survival(PFS) [Up to 3 years after the end of treatment]
3-year PFS rate after treatment
Duration of Response [Up to 3 years after the end of treatment]
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.
Time to Next Treatment [Up to 3 years after the end of 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
Safety of treatment regimens [Up to 3 years after the end of treatment]
Defined as treatment-related toxicity

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Institute of Hematology & Blood Diseases Hospital	Tianjin	Tianjin	China	300020

Sponsors and Collaborators

Institute of Hematology & Blood Diseases Hospital

Investigators

Principal Investigator: Shuhua Yi, Dr., Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College