Neuropathy (nerve pain)
Conditions
Interventions
Zanubrutinib is the study drug and will be used next to standard care. Standard
care is 4 infusions IV of Rituximab or biosimilar infusion per week.
Zanubrutinib will start on the same day as start
Sponsors
Universitair Medisch Centrum Utrecht
Eligibility
Age
18 Years to 99 Years
Inclusion criteria
Inclusion criteria: - Able to provide written informed consent and understand and comply with the requirements of the study - Demyelinating polyneuropathy defined by electrophysiological criteria according to EFNS/PNS PDN guideline, 201019 - Some functional impairment; defined as an iRODS * 44 at baseline - 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 - ECOG performance score 0, 1, or 2 - Adequate hematological laboratory values defined as hemoglobin * 5.0 mmol/L neutrophils > 1.0 × 10^9/L and platelets > 100 × 10^9/L - Adequate hepatic and renal function laboratory values defined as ASAT/ALAT < 3 × ULN, bilirubin < 2.0 × ULN and creatinine clearance * 30 ml/min - 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 MoAb and/or cyclophosphamide is allowed only if given > 6 months before inclusion
Exclusion criteria
Exclusion criteria: - Hematological malignancy e.g known Multiple Myeloma or confirmed Waldenstrom*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 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 - 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 120 days after treatment stop - 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: o QTcF >450 msec (males) o QTcF >460 msec (females) o History of familial long QT syndrome or known family history of Torsades de Pointes o Use of agents known to prolong the QT interval unless they can be permanently discontinued for the duration of the study o 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 - Known infection with human immunodeficiency virus (HIV), or serologic status reflecting active hepatitis B or hepatitis C infection as follows: Presence of hepatitis B surface antigen (HBsAg) or anti*hepatitis B core antibody (anti*HBc). Patients with anti*HBc, but absence of HBsAg, are eligible if hepatitis B virus (HBV) DNA is undetectable and if they are willing to undergo monthly monitoring for HBV reactivation - Presence of hepatitis C virus (HCV) antibody. Patients with presence of HCV antibody are eligible if HCV ribonucleic acid (RNA) is ndetectable - At time of study entry, taking any medications which are strong cytochrome P450, family 3, subfamily A (CYP3A) inhibitors or strong CYP3A inducers - Intolerance to previo
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| To improve the functional neurological outcome of patients, as measured on the RaschbuiltOverall Disability Scale (RODS) for inflammatory neuropathies (iRODS) withZanubrutinib in combination with Rituximab or biosimilar treatment. | — |
Secondary
| Measure | Time frame |
|---|---|
| Safety of combined treatment with Rituximab or biosimilar and Zanubrutinib * Changes in other neurological outcome parameters besides the iRODS, such as ONLS (Overall Neuropathy Limitations Scale), 10 meter walk test, ataxia score, modified INCAT (The Inflammatory Neuropathy Cause And Treatment) sensory sum score (mISS), and grip strength (vigorimetry) 8,14*17 * Percentage of patients with >4 points difference measured with iRODS after 12 cycles of therapy * Hematological response * Change of anti*MAG titers during treatment and follow up * Molecular profiling and relation with response and immunological parameters * Relation between neurological and immunological outcome parameters * Quality of life assessment (EQ*5D*5L) before (at baseline), during and after therapy * Patients global impression of change (PGIC) during and after therapy * Overall survival (OS) * Progression free survival (PFS) (hematological) | — |
Countries
Netherlands
Outcome results
None listed