Zanubrutinib treatment for patients with IgM monoclonal gammopathy and related polyneuropathy

Multicenter, Open-label, Phase II Study in Patients With Immunoglobulin M Monoclonal Gammopathy of Unknown Significance and Myelin Associated Glycoprotein Antibodies Related Polyneuropathy and Zanubrutinib Treatment - MAGNAZ Trial

This study is testing if a new treatment combining Zanubrutinib and Rituximab can help adults with a specific type of nerve damage caused by IgM monoclonal gammopathy feel better.

Quick facts

• Phase: Phase 2
• Study type: Interventional
• Enrollment: 35 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: UMC Utrecht (Academic / other)
• Drugs / interventions: Rituximab, Zanubrutinib, cyclophosphamide, fludarabine, chemotherapy
• Locations: 1 site (Utrecht)
• Trial ID: NCT05939037 on ClinicalTrials.gov

What this trial studies

This phase II clinical trial investigates the effectiveness and safety of Zanubrutinib, combined with Rituximab, in treating patients with immunoglobulin M monoclonal gammopathy of unknown significance (IgM MGUS) and anti-MAG related polyneuropathy. The trial will enroll 42 adult participants from two Dutch hospitals and will assess neurological response rates over a 6-month treatment period, followed by an additional 6 months for those who respond adequately. The study aims to evaluate the hematological response and the impact on clinical outcomes for participants with this chronic and progressive condition.

Who should consider this trial

Good fit: Ideal candidates include adults aged 18 and older with diagnosed IgM MGUS and anti-MAG antibodies, experiencing functional impairment.

Not a fit: Patients without IgM MGUS or those with other forms of polyneuropathy unrelated to anti-MAG antibodies may not benefit from this treatment.

Why it matters

Potential benefit: If successful, this treatment could significantly improve neurological function and quality of life for patients suffering from IgM MGUS-related polyneuropathy.

How similar studies have performed: Previous studies have shown success with BTK inhibitors in related conditions, suggesting a promising avenue for treatment in this patient population.

Eligibility criteria

Inclusion Criteria:

* 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
* Previous treatment with intravenous immunoglobulins is allowed if \> 3 months before inclusion
* Previous treatment for PNP with Anti CD20 monoclonal antibody (MoAb) and/or cyclophosphamide is allowed only if given \> 6 months before inclusion. Patients without previous response to Rituximab \>6 months before inclusion can be included.

Exclusion Criteria:

* 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)
  * History of familial long QT syndrome or known family history of Torsade de Pointes
  * Use of agents known to prolong the QT interval unless they can be permanently discontinued for the duration of the study
  * Second degree atrioventricular (AV) block Type II, or third-degree AV block
  * Controlled atrial fibrillation is allowed
* Unable to swallow capsules or disease significantly affecting gastrointestinal function such as malabsorption syndrome, resection of the stomach or small bowel, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction
* Uncontrolled active systemic infection or recent infection requiring parenteral anti-microbial therapy that was completed ≤ 14 days before the first dose of study drug. Active tuberculosis.
* Infection with human immunodeficiency virus (HIV), or serologic status reflecting active hepatitis B or hepatitis C infection. Patients with presence of hepatitis C virus (HCV) antibody are eligible if HCV ribonucleic acid (RNA) is undetectable. Patients with a serologic status reflecting prior or active hepatitis B cannot be included. We will test the hepatitis B surface antigen (HBsAg), anti-hepatitis B core antibodies (anti-HBc) and anti-hepatitis B surface antibodies (anti-HBs) at screening. Patients with a serological status reflecting an earlier hepatitis B vaccination (HBsAg negative / antiHBc negative / anti-HBs positive) may be included. Other combinations are not allowed.
* At time of study entry, taking any medications which are strong Cytochrome P450, family 3, subfamily A (CYP3A) inhibitors (e.g., conivaptan, posaconazole, voriconazole, ketoconazole, itraconazole, clarithromycin, indinavir, lopinavir, ritonavir, telaprevir) or strong CYP3A inducers (e.g., carbamazepine, phenytoin, rifampin, St. John's wort)
* Intolerance to previous Rituximab treatment
* History of intolerance to the active ingredients or other ingredients of Zanubrutinib

Where this trial is running

Utrecht

• University Medical Center Utrecht — Utrecht, Netherlands (Recruiting)

Conditions Monoclonal Gammopathy of Uncertain Significance