Zanubrutinib Treatment in Patients With IgM Monoclonal Gammopathy and Antri-MAG Related Polyneuropathy

NCT05939037 | Recruiting Phase 2

• 1 other identifier: 22U-0179
• Study Type: interventional
• Target: 35
• Locations: 1 country
• Sites: 1

Brief Summary

The objective of this investigator-initiated phase II single-arm open-label clinical trial is to investigate neurological response rate, safety and tolerability of Zanubrutinib 320 mg daily in combination with Rituximab 375 mg/m2 (standard therapy) for the treatment of immunoglobulin M monoclonal gammopathy of unknown significance (IgM MGUS) related polyneuropathy with Myelin Associated Glycoprotein antibodies (anti-MAG). 42 adult patients will be included in two Dutch hospitals (University Medical Center Utrecht and Amsterdam University Medical Center). This trial consists of a 6-month treatment period, after which the hematological response will be evaluated. Adequately responding participants (at least partial response) will be treated for an additional 6 months, after which hematological response will be re-evaluated. Participants with at least a very good partial response will remain on treatment. Non-responding participants will be followed for clinical outcomes only. The total study period per participant will be 36 months.

Conditions

Monoclonal Gammopathy of Uncertain Significance

Outcome Measures

Primary Outcomes (3)

• Proportion of patients with ≥2 points improvement on the INCAT disability score

  To assess the improvement of the functional neurological outcome of participants after treatment with Zanubrutinib in combination with Rituximab by The Inflammatory Neuropathy Cause and Treatment (INCAT) disability score (Overall score is the sum of arm and leg disability, scaled 0 (no problems) to 5 (disabled). A proportion of patients with ≥2 points improvement on the INCAT disability score wil be used as primary endpoint

  At the end of Cycle 12 (each cycle is 28 days)

• Incidence of adverse events during treatment and follow up by the Common Terminology Criteria for Adverse Events (CTCAE), version 5

  To assess the safety and tolerability of the combined treatment with Rituximab and Zanubrutinib

  Till 36 months from baseline

• Study Drug adherence

  Dose adjustments made per patient.Registration of drug accountability (counting of remaining capsules after each treatment cycle). Drug accountability will be presented as percentage.

  Till end of treatment, which will be after 6 or 12 cycles (each cycle is 28 days)

Interventions

Zanubrutinib Oral Product DRUG

Treatment will consist of Rituximab administered at 375 mg/m2 intravenously on Cycle 1 Days 1, 8, 15, 22 only (4 total infusions). The experimental part of the treatment will consist of Zanubrutinib, given once daily 320 mg (4 x 80 mg capsules). Although Zanubrutinib is taken continuously, therapy cycles are calculated per 28 days. Participants will be treated for a minimum of 6 cycles per protocol. Participants who still use Zanubrutinib at the end of study can continue indefinitely until registration and reimbursement in the Netherlands.

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Able to provide written informed consent and understand and comply with the requirements of the study
• Demyelinating PNP defined by the European Federation of Neurological Societies/Peripheral Nerve Society guideline on management of paraproteinemic demyelinating neuropathies (84)
• Functional impairment; defined as an INCAT disability score (INCATds) of ≥2
• Age ≥ 18 years
• IgM MGUS, defined as the presence of an IgM M-protein (detectable but \< 30 g/L) AND elevated total IgM level in serum
• Presence of anti MAG antibodies ≥ 10.000 titer units, measured with the Bühlmann ELISA
• Eastern Cooperative Oncology Group (ECOG) performance score 0, 1, or 2 (85)
• Adequate hematological laboratory values defined as hemoglobin ≥ 6.0 mmol/L, neutrophils \> 1.0 × 109/L and platelets \> 100 × 109/L
• Adequate hepatic and renal function laboratory values defined as aspartate transaminase (ASAT)/ alanine aminotransferase (ALAT) \< 3 × upper limit of normal (ULN), bilirubin \< 1.5× ULN and creatinine clearance ≥ 30 ml/min
• Patients with hypertension can only be enrolled when blood pressure is adequately treated, defined as systolic blood pressure of \<140 mmHg and diastolic blood pressure of \<90 mmHg at screening
• No history of severe bleeding disorder such as hemophilia A, hemophilia B, von Willebrand disease, or history of spontaneous bleeding requiring blood transfusion or other medical intervention

You may not qualify if:

• Hematological malignancy e.g., known Multiple Myeloma or confirmed Waldenström's Macroglobulinemia based on bone marrow analysis
• Any history of malignancy of any organ system (other than localized basal or squamous cell carcinoma of the skin, superficial bladder cancer or carcinoma in situ of the cervix or breast), treated or untreated within the last 3 years
• History of ischemic stroke within 180 days before first dose of Zanubrutinib
• History of central nervous system (CNS) hemorrhage
• History of inherited or acquired hemorrhagic disorder
• Prior treatment with purine analogues (fludarabine or cladribine)
• Prior treatment with a BTK inhibitor
• Major surgery within 4 weeks of study treatment
• Participation in another interventional clinical trial
• Pregnant women, women with child-bearing potential (WOCBP) not able or willing to prevent pregnancy and lactating women as well. WOCBP will agree to use highly effective contraception for the duration of the trial treatment and for 12 months after Rituximab treatment stop or 120 days after Zanubrutinib treatment stop, whichever has a longer duration. Participants using hormonal contraceptives (e.g., birth control pills or devices) must use a barrier method of contraception (e.g., condoms) as well.
• Other known concomitant causes of chronic (demyelinating) PNP, including Charcot Marie Tooth Disease, other hereditary neuropathies, diabetes mellitus, use of amiodarone, past or current dependence on alcohol, other lymphoma or malignant blood dyscrasias, previous Guillain-Barré syndrome
• Currently active, clinically significant cardiovascular disease such as uncontrolled arrhythmia, congestive heart failure, any Class 3 or 4 cardiac disease (congestive heart failure) as defined by the New York Heart Association (NYHA) Functional Classification, or history of myocardial infarction within 6 months of screening
• A history of clinically significant ECG abnormalities, or any of the following ECG abnormalities at screening:
• The corrected QT interval by Fridericia (QTcF) \>450 msec (males)
• QTcF \>460 msec (females)

Sponsors & Collaborators

• UMC Utrecht: lead
• BeiGene: collaborator

Study Sites (1)

University Medical Center Utrecht

Utrecht, Utrecht, 3584CX, Netherlands

RECRUITING

MeSH Terms

Conditions

Monoclonal Gammopathy of Undetermined Significance

Condition Hierarchy (Ancestors)

Hypergammaglobulinemia; Blood Protein Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Paraproteinemias; Immunoproliferative Disorders; Immune System Diseases

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principle Investigator

Study Record Dates

• First Submitted: May 23, 2023
• First Posted: July 11, 2023
• Study Start: March 1, 2024
• Primary Completion: October 1, 2025
• Study Completion (Estimated): October 1, 2027
• Last Updated: April 8, 2025

Record last verified: 2025-04

Locations

NL (1)