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
试验速览
- 阶段
- 2 期
- 状态
- 进行中（未招募）
- 发起方
- UMC Utrecht
- 入组人数
- 35
- 试验地点
- 2
- 主要终点
- Study Drug adherence
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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.
排除标准
- •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
结局指标
主要结局
Study Drug adherence
时间窗: Till end of treatment, which will be after 6 or 12 cycles (each cycle is 28 days)
Dose adjustments made per patient.Registration of drug accountability (counting of remaining capsules after each treatment cycle). Drug accountability will be presented as percentage.
Incidence of adverse events during treatment and follow up by the Common Terminology Criteria for Adverse Events (CTCAE), version 5
时间窗: Till 36 months from baseline
To assess the safety and tolerability of the combined treatment with Rituximab and Zanubrutinib
Proportion of patients with ≥2 points improvement on the INCAT disability score
时间窗: At the end of Cycle 12 (each cycle is 28 days)
To assess the improvement of the functional neurological outcome of participants after treatment with Zanubrutinib in combination with Rituximab by The Inflammatory Neuropathy Cause and Treatment (INCAT) disability score (Overall score is the sum of arm and leg disability, scaled 0 (no problems) to 5 (disabled). A proportion of patients with ≥2 points improvement on the INCAT disability score wil be used as primary endpoint
次要结局
未报告次要终点
研究者
Klaartje Nijssen
Principle Investigator
UMC Utrecht