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

SYNOPSIS 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

Rationale Polyneuropathy (PNP) associated with immunoglobulin M (IgM) monoclonal gammopathy of unknown significance (MGUS) and myelin associated glycoprotein (MAG) antibodies (IgM MGUS/anti-MAG PNP) is characterized by severe sensory dysfunction, ataxia, imbalance, tremor and distal weakness of the arms and legs. It is a chronic and progressive PNP that leads to significant disability. The IgM M-protein that is produced by the MGUS B-cell clone has anti-MAG properties, and treatment options are aimed at lowering the M protein level. Treatment response is associated with a decrease in M-protein and anti-MAG antibodies. At present, the only treatment option is Rituximab (an anti-cluster of differentiation antigen 20 (CD20) monoclonal antibody), which effectuates a limited but clinically meaningful neurological improvement in approximately 30% of patients.

IgM MGUS/anti-MAG PNP shares in many cases the same genetic mutation in the MYD88 gene as seen in Waldenström's Macroglobulinemia (WM). This mutation is associated with an enhanced sensitivity to a novel type of drugs: Bruton's Tyrosine Kinase (BTK) inhibitors. WM patients have recently been successfully treated with BTK inhibitors. One of these BTK inhibitors, Zanubrutinib, has been given to many patients with hematological malignancies and is considered a safe drug. In WM, Zanubrutinib lowers the IgM levels with minimal 50% in 77% of patients. It has been approved for several malignancies in Europe and the USA. Importantly, and in contrast to other drugs, chemotherapy induced PNP is not a side effect. Considering the genetic link between IgM MGUS/anti-MAG PNP and WM, the investigators postulate that BTK-inhibitors are also able to effectively treat IgM MGUS/anti-MAG PNP and alleviate the severe neurological symptoms.

Objective The investigators want to investigate the use of Zanubrutinib in combination with standard therapy Rituximab for the possible improvement on the neurological outcome in patients with IgM MGUS/anti-MAG PNP. In addition, the investigators want to investigate safety and tolerability of this treatment.

Main trial endpoints As main endpoints, the investigators aim to explore initial improvement of neurological disability after 12 months and safety and tolerability of Zanubrutinib treatment. For the neurological primary endpoint, neurological disability will be measured with the Inflammatory Neuropathy Cause and Treatment (INCAT) disability score. The investigators will use proportion of patients with ≥2 points improvement on the INCAT disability score as primary endpoint. For safety and tolerability, the investigators will determine the rate of treatment related adverse events classified according to the Medical Dictionary for Regulatory Activities and graded according to the Common Terminology Criteria for Adverse Events version 5.0 and dose changes, and the investigators will evaluate adherence to Zanubrutinib by counting early withdrawals.

Secondary trial endpoints Secondary endpoints include patient reported outcome measures (PROM's) and other neurological function measurements and hematological response rate. In addition, the investigators will evaluate molecular mutations and the change in anti MAG titers.

Trial design This is an investigator-initiated, phase 2a, single-arm, open-label clinical trial to investigate whether the combined treatment of Zanubrutinib and Rituximab can be a potentially beneficial treatment of IgM MGUS/anti-MAG PNP, what the expected effect size of this treatment on IgM MGUS/anti-MAG PNP is to possibly inform a larger randomized controlled trial, and whether this treatment is safe and tolerable. In total, 2 hospitals in the Netherlands will participate to enroll 42 patients. The accrual period will consist of 1 year. The study will consist 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. participants will visit the clinic every month during the first 6 months, every 2 months during the subsequent 6 months and every 3 months during the follow-up period. Each visit will take approximately 1 hour.

Trial population Patients of 18 years and older with established IgM MGUS/anti-MAG PNP following the standard criteria may be eligible for the trial. All patients must have signed an informed consent to be registered before start of treatment and must meet all eligibility criteria.

Interventions Treatment 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.

Diagnostic procedures At the first visit, the investigators will screen for trial eligibility, which includes a bone marrow aspiration and biopsy, electrocardiogram (ECG), medical history inquiry including prior medicine usage, physical examination, neurological examination including questionnaires, urine analysis, pregnancy test and blood tests. Every visit, the investigators will obtain a blood sample to measure the pharmacodynamic response and monitor treatment safety. Additionally, the investigators will perform physical examinations and neurological examinations (including questionnaires) to monitor treatment effect.

Ethical considerations relating to the clinical trial including the expected benefit to the individual participant or group of patients represented by the trial participants as well as the nature and extent of burden and risks This trial investigates the potential positive effect of Zanubrutinib on a severe progressive neurological disease by lowering the disease-causing IgM M protein. For this disabling disease there is currently limited effective treatment. Zanubrutinib is an approved medicine that has been used for associated hematological malignancies such as WM. Side effects are regarded acceptable. Potential benefits are on the individual level, which is reflected by one of the main endpoints that reflects neurological functional improvement. Since this trial investigates Zanubrutinib treatment for a disease wherein it is not approved at present, the investigators will closely monitor safety and response by means of frequent blood analyses and outpatient clinic visits.