A Phase 2 Clinical Trial to Evaluate Zanubrutinib Combined With BR (Bendamustine/Rituximab) Regimen in Subjects With Newly-diagnosed Waldenström's Macroglobulinemia (CZ-WM01)

• ClinicalTrials.gov Identifier: NCT05979948
• Recruitment Status: Recruiting
• First Posted: August 7, 2023
• Last Update Posted: September 14, 2023
• Sponsor: Shanghai Changzheng Hospital
• Collaborators: RenJi Hospital; Huashan Hospital; Shanghai 6th People's Hospital; Huadong Hospital
• Information provided by (Responsible Party): Juan Du, Shanghai Changzheng Hospital

Study Description

Brief Summary:

This was a single-arm, multicenter, Phase 2 study to evaluate the efficacy of zanubrutinib combined with BR (Bendamustine/Rituximab) regimen in Chinese participants with newly-diagnosed Waldenström's macroglobulinemia who exhibited one or more of the criteria for requiring treatment based on consensus guidelines from the 11th International Workshop on Waldenström's Macroglobulinemia (IWWM). The investigators propose this combination will improve the deep remission compared to single Zanubrutinib or BR regimen and can be a time-limited regimen which will reduce the life-time therapy and benefit the patients.

Condition or disease	Intervention/treatment	Phase
Waldenström's Macroglobulinemia	Drug: Zanubrutinib; Drug: Bendamustine; Drug: Rituximab	Phase 2

Detailed Description:

The study comprised an initial screening phase (up to 7 days), a single-arm treatment phase, and a follow-up phase. Subjects with newly-diagnosed Waldenström's macroglobulinemia can participate if all eligibility criteria are met. The participants will receive bendamustine and rituximab for 6 28-day cycles. Bendamustine will be given intravenously at 70-90 mg/m2 on days 1 and 2 of each cycle. Rituximab will be given on day 1 of each cycle (375 mg/m2 intravenously), Zanubrutinib will be given orally 160mg Bid per day, up to 12 months. The participants with WM will also have disease assessment with Lymph node ultrasound and abdominal ultrasound each cource, serum IgM, serum protein electrophoresis (SPE), immunofixation (IFA), and viscosity assessments will be measured serially. A bone marrow aspiration and biopsy flow cytometry examination will be done before treatment and at response assessment at cycle 6 and 12. Durability of response will also be assessed every 3 months after treatment.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 60 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Prospective, Open-label, Multicenter Study of Zanubrutinib Combined With BR (Bendamustine/Rituximab) Regimen in Subjects With Newly-diagnosed Waldenström's Macroglobulinemia
• Actual Study Start Date: August 1, 2023
• Estimated Primary Completion Date: April 1, 2025
• Estimated Study Completion Date: December 1, 2025

Arms and Interventions

Arm	Intervention/treatment
Experimental: zanubrutinib combined with BR regimen; Drug: zanubrutinib,160 mg oral capsules twice daily for 12 months Drug: Bendamustine,70-90 mg/m2 on days 1 and 2 of each cycle for 6 cycles. Drug: Rituximab,375 mg/m2 intravenously on day 0 of each cycle for 6 cycles.	Drug: Zanubrutinib; Zanubrutinib, 160 mg oral capsules twice daily for 12 months; Drug: Bendamustine; Bendamustine, 70-90 mg/m2 on days 1 and 2 of each cycle for 6 cycles.; Drug: Rituximab; Rituximab, 375 mg/m2 intravenously on day 0 of each cycle for 6 cycles

Outcome Measures

Primary Outcome Measures :

1. Overall Response Rate (ORR) [ Time Frame: up to the end of 12 cycles of treatment(each cycle is 28 days) ]
   ORR is defined as the percentage of participants with a minor, partial, very good partial, and complete response
2. The best deep response rate [ Time Frame: Time Frame: up to the end of 12 cycles of treatment(each cycle is 28 days) ]
   defined as complete response (CR) and very good partial response (VGPR)

Secondary Outcome Measures :

1. Progression-free Survival (PFS) [ Time Frame: Up to 6 years post first dose ]
   PFS was defined as from the initiation of treatmentuntil to first documentation of progression or death, whichever comes first.
2. Overall Survival (OS) [ Time Frame: Up to 6 years post first dose ]
   OS is measured from the date of the initial of treatment to the date of the subject's death.
3. minimal residual disease (MRD) rate [ Time Frame: Up to 6 years post first dose ]
   MRD will be assessed at two on treatment timepoints (before start of cycles 7, 12) and every 6 months thereafter. MRD will be measured through bone marrow samples using flow cytometrey.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 75 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

Subjects must meet all of the following criteria to be enrolled:

1. Newly diagnosed patients with waldenström's macroglobulinemia meeting at least one criterion for treatment according to consensus panel criteria from the eleventh IWWM.
2. ECOG score: 0-3 points, estimated survival time exceeding 3 months.
3. Did not receive any treatment for Waldenström's macroglobulinemia before screening, except for glucocorticoid therapy for autoimmune hemolysis.
4. No serious damage to main organs, and meet the following laboratory examination indicators: creatinine clearance rate≥40ml/min, total bilirubin≤1.5 times of the upper limit of normal range; AST and ALT≤2.5 times of the upper limit of normal range; Myocardial enzyme≤2 times of the upper limit of normal range; ECHO must demonstrate left ventricular ejection fraction (LVEF) within the normal range, and no ECG abnormality with clinical significance.
5. Neutrophil count≥1.5×10^9/L without growth factor therapy within 7 days before screening; Platelet count≥50×10^9/L without growth factor support or transfusion within 7 days before screening; Hemoglobin≥60 g/L without erythropoietin (EPO) support or transfusion within within 7 days before screening.
6. No history of paroxysmal atrial fibrillation or chronic persistent atrial fibrillation.
7. Able to swallow and Oral administration.
8. The subjects complete all screening and evaluations listed in all trial protocols.
9. The subjects who signed the informed consent form for chemotherapy.

Exclusion Criteria:

1. Waldenström's macroglobulinemia with amyloidosis or POEM syndrome
2. HIV positive, or patients with active hepatitis A, hepatitis B, and hepatitis C infection; Or the number of copies of hepatitis B virus>10^2.
3. Accompanied by other serious unstable diseases, including heart failure, renal failure, liver failure, hemorrhagic diseases, uncontrollable diabetes, etc.
4. In the past two years, the terminal organ was damaged due to autoimmune diseases (such as Crohn's disease, rheumatoid arthritis, systemic lupus erythematosus), or the systemic use of immunosuppressive or other systemic disease control drugs was required.
5. Serious infectious diseases (uncured pulmonary tuberculosis, pulmonary aspergillosis, etc.).
6. Other uncontrolled malignancies (excluding non Melanoma skin cancer, cervical cancer in situ, bladder cancer cancer and breast cancer with disease-free survival of more than 5 years).
7. Individuals with epilepsy, dementia, and other mental disorders who require medication treatment and are unable to understand or follow the research protocol.
8. Drug use, medical, psychological, or social conditions that may interfere with participants' participation in the study or evaluation of the results.
9. Pregnant and lactating women.
10. Patients who are accounted to be not appropriate for this trail by investigator.

Contacts and Locations

Contacts

Contact: Haiyan He, Master; +8613661513012; doctorhehaiyan@126.com

Locations

China, Shanghai

Shanghai Changzheng Hospital; Recruiting

Shanghai, Shanghai, China, 200020

Contact: Juan Du, Doctor +86 02181885424 Juan_du@live.com

Contact: Haiyan He, Master +86 13661513012 doctorhehaiyan@126.com

Sponsors and Collaborators

Shanghai Changzheng Hospital

RenJi Hospital

Huashan Hospital

Shanghai 6th People's Hospital

Huadong Hospital

Investigators

• Principal Investigator: Juan Du, Doctor; Shanghai Changzheng Hospital

More Information

• Responsible Party: Juan Du, Director, Shanghai Changzheng Hospital
• ClinicalTrials.gov Identifier: NCT05979948
• Other Study ID Numbers: CZ-WM01
• First Posted: August 7, 2023
• Last Update Posted: September 14, 2023
• Last Verified: September 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Juan Du, Shanghai Changzheng Hospital:

Waldenström's macroglobulinemia; Zanubrutinib; BR regimen; newly-diagnosed

Additional relevant MeSH terms:

Waldenstrom Macroglobulinemia; Neoplasms, Plasma Cell; Neoplasms by Histologic Type; Neoplasms; Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Paraproteinemias; Blood Protein Disorders; Hematologic Diseases; Hemorrhagic Disorders; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Rituximab; Bendamustine Hydrochloride; Zanubrutinib; Antineoplastic Agents, Immunological; Antineoplastic Agents; Immunologic Factors; Physiological Effects of Drugs; Antirheumatic Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Molecular Mechanisms of Pharmacological Action; Tyrosine Kinase Inhibitors; Protein Kinase Inhibitors; Enzyme Inhibitors