Zanubrutinib Treatment in Patients With IgM Monoclonal Gammopathy and Antri-MAG 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
UMC Utrecht
35 participants
Mar 1, 2024
INTERVENTIONAL
Conditions
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.
Eligibility
Inclusion Criteria13
- 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 Criteria25
- 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
Interested in this trial?
Get notified about updates and connect with the research team.
Interventions
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.
Locations(1)
View Full Details on ClinicalTrials.gov
For the most up-to-date information, visit the official listing.
NCT05939037