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

Overview

Sponsor-declared trial summary

Key facts

Sponsor

University Medical Center Utrecht

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Nervous System Diseases [C10], Diseases [C] - Hemic and Lymphatic Diseases [C15]

Trial duration

13 Mar 2024 → ongoing

Decision date (initial)

2023-10-27

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

No

Funding sources

Dr. C.J. Vaillant Fonds · BeiGene Switzerland GmbH

External identifiers

EU CT number

2023-505933-29-00

ClinicalTrials.gov

NCT05939037

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Therapy

We want to investigate the use of Zanubrutinib in combination with standard therapy Rituximab for the possible improvement on the neurological outcome in patients with immunoglobulin M (IgM) monoclonal gammopathy of unknown significance (MGUS) anti-MAG polyneuropathy after 12 months, based on the Inflammatory Neuropathy Cause and Treatment (INCAT) disability score. In addition, we want to investigate safety, tolerability and drug adherence of this treatment.

Secondary objectives 9

1. To assess the hematological response of participants during treatment with Zanubrutinib in combination with Rituximab
2. To assess the improvement of the functional neurological outcome of participants after treatment with Zanubrutinib in combination with Rituximab
3. To assess the hematological progression free survival (PFS) and time to progression (TTP) of participants during and after treatment with Zanubrutinib in combination with Rituximab
4. To assess overall survival of participants after treatment with Zanubrutinib in combination with Rituximab
5. To assess the change of anti-MAG titers during treatment and follow-up of participants treated with Zanubrutinib in combination with Rituximab
6. To assess the molecular profiling and the relation with neurological and hematological response and immunological parameters
7. To assess the timing and duration of both hematological and neurological responses
8. To assess the quality of life of participants before, during and after treatment with Zanubrutinib in combination with Rituximab
9. To assess the global impression of change of participants during and after treatment with Zanubrutinib in combination with Rituximab

Conditions and MedDRA coding

IgM monoclonal gammopathy of unknown significance (MGUS) and myelin associated glycoprotein (MAG) antibodies associated polyneuropathy

Regulatory references

Scientific advice from competent authorities

Vereniging Spierziekten Nederland

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 12

1. Able to provide written informed consent and understand and comply with the requirements of the study
2. Demyelinating polyneuropathy defined by the European Federation of Neurological Societies (EFNS) / Peripheral Nerve Society (PNS) guideline on management of paraproteinemic demyelinating neuropathies
3. Functional impairment; defined as an Inflammatory Neuropathy Cause and Treatment disability score (INCATds) of ≥2
4. Age ≥ 18 years
5. IgM monoclonal gammopathy of unknown significance (MGUS), defined as the presence of an IgM M-protein (detectable but < 30 g/L) AND elevated total IgM level in serum
6. Presence of anti MAG antibodies ≥ 10.000 titer units, measured with the Bühlmann ELISA
7. Eastern Cooperative Oncology Group (ECOG) performance score of 0, 1 or 2
8. Adequate hematological laboratory values defined as hemoglobin ≥ 6.0 mmol/L, neutrophils > 1.0 × 10^9/L and platelets > 100 × 10^9/L
9. Adequate hepatic and renal function laboratory values defined as ASAT/ALAT < 3 × upper limit of normal (ULN), bilirubin < 1.5× ULN and creatinine clearance ≥ 30 ml/min
10. 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
11. Previous treatment with intravenous immunoglobulins is allowed if > 3 months before inclusion
12. Previous treatment for polyneuropathy 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 20

1. Hematological malignancy e.g., known Multiple Myeloma or confirmed Waldenström’s Macroglobulinemia based on bone marrow analysis
2. 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.
3. Other known concomitant causes of chronic (demyelinating) polyneuropathy, 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
4. 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
5. A history of clinically significant ECG abnormalities, or any of the following ECG abnormalities at screening: 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.
6. 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
7. History of ischemic stroke within 180 days before first dose of Zanubrutinib
8. History of central nervous system (CNS) hemorrhage
9. History of inherited or acquired hemorrhagic disorder
10. Prior treatment with purine analogues (fludarabine or cladribine)
11. Prior treatment with a Bruton's tyrosine kinase (BTK) inhibitor
12. Major surgery within 4 weeks of study treatment
13. Participation in another interventional clinical trial
14. 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
15. Uncontrolled active systemic infection or recent infection requiring parenteral anti-microbial therapy that was completed ≤ 14 days before the first dose of study drug
16. Active tuberculosis
17. 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.
18. At time of study entry, taking any medications which are strong 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)
19. Intolerance to previous Rituximab treatment
20. History of intolerance to the active ingredients or other ingredients of Zanubrutinib

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 4

1. Proportion of patients with ≥2 points improvement on the Inflammatory Neuropathy Cause and Treatment disability score (INCATds) at the end of cycle 12 (1 year from baseline)
2. Incidence of adverse events during treatment and follow up (36 months from baseline), graded by the Common Terminology Criteria for Adverse Events (CTCAE), version 5.0
3. Dose adjustments made per patient
4. Registration of drug accountability (counting of remaining capsules after each treatment cycle). Drug accountability will be presented as percentage.

Secondary endpoints 22

1. Hematological response rate (including progression) at 6, 12, 24 and 36 months
2. Best achieved hematological response rate during treatment and follow-up
3. Change from baseline on the Inflammatory Neuropathy Cause and Treatment disability score (INCATds) after 3, 6, 10, 12, 18, 24 and 36 months, at the end of treatment and the end of study
4. Change from baseline on the Rasch-built Overall Disability Scale for immune-mediated peripheral neuropathies (iRODS) after 3, 6, 10, 12, 18, 24 and 36 months, at the end of treatment and the end of study
5. Change from baseline on the Overall Neuropathy Limitations Scale (ONLS) after 3, 6, 10, 12, 18, 24 and 36 months, at the end of treatment and the end of study
6. Change from baseline on the 10 meter walk test after 3, 6, 10, 12, 18, 24 and 36 months, at the end of treatment and the end of study
7. Change from baseline on the ataxia score after 3, 6, 10, 12, 18, 24 and 36 months, at the end of treatment and the end of study
8. Change from baseline on the modified Inflammatory Neuropathy Cause And Treatment (INCAT) sensory sum score after 3, 6, 10, 12, 18, 24 and 36 months, at the end of treatment and the end of study
9. Change from baseline on the grip strength (vigorimetry) after 3, 6, 10, 12, 18, 24 and 36 months, at the end of treatment and the end of study
10. Registration of hematological progression (and other responses) during treatment and follow-up to assess hematological progression free survival and time to progression
11. Death registration during treatment and follow up. Overall survival is defined as time from inclusion to death (or end of follow-up)
12. Change from baseline in Bühlmann ELISA titer units, measured after every 2 cycles during treatment and every 6 months during follow-up
13. Evaluation of molecular markers at diagnosis. Performed using next generation sequencing (NGS) for CXCR4 mutations and the MYD88L265P mutation after CD19 selection of bone marrow aspirate at central laboratory.
14. At baseline, a complete panel of anti-neural antibodies will be performed (only if not done previously), that consists of gangliosides GM1, GM2, GD1a and GD1b.
15. Relation of neurological and hematological response endpoints with molecular markers at diagnosis.
16. Relation of molecular markers with anti-MAG titer
17. Time to first hematological and first neurological response
18. Time to maximum hematological and maximum neurological response
19. Duration of hematological and neurological response during follow up period
20. Relation of immunological parameters with neurological endpoints
21. Change from baseline on the quality of life assessment (EQ-5D-5L) measured after 6, 12, 18, 24, 30 and 36 months, at the end of treatment and the end of study
22. Change from baseline on the patients global impression of change (PGIC) assessment, measured after 6, 12, 18, 24, 30 and 36 months, at the end of treatment and the end of study

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

University Medical Center Utrecht

Sponsor organisation

University Medical Center Utrecht

Address

Heidelberglaan 100

City

Utrecht

Postcode

3584 CX

Country

Netherlands

Scientific contact point

Organisation

University Medical Center Utrecht

Contact name

Clinical trial management hematology

Public contact point

Organisation

University Medical Center Utrecht

Contact name

Clinical trial management hematology

Locations

1 EU/EEA country · 2 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 11 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

7 submissions — initial application plus substantial / non-substantial modifications