The objective of this investigator-initiated phase II single-arm open-label clinicaltrial is to investigate neurological response rate, safety and tolerability ofZanubrutinib 320 mg daily in combination with Rituximab 375 mg/m2 (standard therapy) forthe treatment of immunoglobulin M monoclonal gammopathy of unknown significance (IgMMGUS) related polyneuropathy with Myelin Associated Glycoprotein antibodies (anti-MAG).42 adult patients will be included in two Dutch hospitals (University Medical CenterUtrecht and Amsterdam University Medical Center). This trial consists of a 6-monthtreatment period, after which the hematological response will be evaluated. Adequatelyresponding participants (at least partial response) will be treated for an additional 6months, after which hematological response will be re-evaluated. Participants with atleast a very good partial response will remain on treatment. Non-responding participantswill be followed for clinical outcomes only. The total study period per participant willbe 36 months.
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.
Drug: Zanubrutinib Oral Product
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.
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
University Medical Center Utrecht
Utrecht, Netherlands
Investigator: Max Van de Mortel
Contact: +31887555878
hemat-research@umcutrecht.nl
Not Provided