Zanubrutinib in Primary Cold Agglutinin Disease

NCT06067048 | Active Not Recruiting Phase 2 DMC

• 1 other identifier: HO169
• Study Type: interventional
• Target: 25
• Locations: 4 countries
• Sites: 10

Brief Summary

Cold agglutinin disease (CAD) is defined as a chronic autoimmune hemolytic anemia (AIHA) with a monospecific direct antiglobulin test (DAT) strongly positive for C3d and the presence of cold agglutinins (CA; titer ≥ 64 at 4°C). Patients may have a B-cell clonal lymphoproliferative disorder (LPD) detectable in blood or marrow but no clinical or radiological evidence of malignancy. CAD can lead to AIHA, peripheral ischemic symptoms (cold-induced peripheral symptoms such as acrocyanosis etc.), or both. The CAs are typically monoclonal IgM antibodies produced by the clonal B-cells, usually IgM kappa with specificity for the I antigen on erythrocytes. There is no curative treatment. Current treatment options include rituximab monotherapy, however this has only a limited and short-lasting effect. Rituximab in combination with chemotherapy induces deeper and more durable responses, however since CAD patients typically do not have an overt malignancy this comes with concerns about short- and long-term toxicity. Novel complement inhibitors may be effective for the hemolysis but are not expected to be effective against cold induced peripheral symptoms while this is directly IgM mediated. Bruton Tyrosine Kinase inhibitors (BTKis) are effective in many B-cell lymphoproliferative disorders including the IgM producing clone of Waldenström macroglobulinemia (WM) and were very effective on both AIHA and peripheral ischemic symptoms in patients with CAD based on retrospective data.

Conditions

Lymphoma

Outcome Measures

Primary Outcomes (1)

• CAD response rate (PR or CR) after 6 cycles of zanubrutinib treatment

  1 year

Secondary Outcomes (9)

• Rate of CAD response categories (CR, PR or none; separately) after 6 cycles of treatment and best CAD response on protocol

  3 years

• Time to CAD response and time to best CAD response.

  3 years

• Hematological response rates after 6 cycles, as per the classification criteria defined by the IWWM-6.

  3 years

• Best hematological response rates on protocol, as per the classification criteria defined by the IWWM-6

  3 years

• Duration of CAD response and duration of hematological response

  3 years

Other Outcomes (10)

• Progression free survival, defined as time from registration to relapse of CAD or death from any cause, whichever comes first

  3 years

• Time to next CAD treatment (off protocol).

  3 years

• Overall survival, defined as time from registration to death from any cause. Patients alive will be censored at the date of last contact.

  3 years

Study Arms (1)

Treatment arm

EXPERIMENTAL

Zanubrutinib, 320 mg per day (four 80 mg capsules)

Drug: Zanubrutinib Oral Capsule

Interventions

Zanubrutinib Oral Capsule DRUG

36 cycles (1 cycle is 28 days)

Also known as: Brukinsa

Treatment arm

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• In order to be eligible to participate in this study, a patient must meet all of the following criteria:
• CAD diagnosis defined by the combination of:
• Chronic hemolysis (\>3 months; suppressed haptoglobin) and
• Cold agglutinin titer of 64 or higher at 4°C and
• Positive direct antiglobulin test, strongly positive (at least 2+) with anti-C3d and negative or weakly positive (maximum 2+) with anti-IgG,
• AND:
• The presence of a clonal B-cell lymphoproliferative disorder defined by:
• M-protein by serum electrophoresis confirmed by immunofixation, and/or
• A clonal CD20 positive lymphocyte population in the bone marrow (a very small clone visible only by flow cytometry is allowed)
• Indication for therapy:
• Hb ≤ 10.5 g/dL
• AND/OR
• Considerable CIPS (grade 2 or more; see appendix E)
• Relapsed or refractory after at least one prior CAD treatment, OR is treatment naïve and not eligible for currently available treatment options, per clinician's judgement.
• Age ≥ 18 years.

You may not qualify if:

• A patient who meets any of the following criteria cannot be included in this study:
• Cold agglutinin syndrome (CAS) secondary to specific infection (Mycoplasma or Epstein-Barr virus) or rheumatological disorders
• Mixed AIHA, Evans syndrome (concurrent autoimmune thrombocytopenia/ITP).
• Prior non-lymphatic malignant disease within the past 3 years, except for curatively treated basal or squamous cell skin cancer, non-muscle-invasive bladder cancer, carcinoma in situ of the cervix or breast, or localized Gleason score 6 prostate cancer.
• History of severe bleeding disorder such as hemophilia A, hemophilia B, von Willebrand disease, or history of unexplained spontaneous bleeding requiring blood transfusion or other medical intervention.
• History of stroke or intracranial hemorrhage within 6 months before first dose of study drug.
• Previous treatment with BTKi.
• Major surgery within 4 weeks of the first dose of study drug.
• Requiring ongoing treatment with warfarin or warfarin derivatives. Please note: Patients being treated with DOACs (e.g., apixaban, edoxaban or rivaroxaban) or antiplatelet therapy can be included, but must be properly informed about the increased risk of hemorrhage under treatment with zanubrutinib.
• Requiring ongoing treatment with a moderate or strong CYP3A inducer. Patients requiring ongoing treatment with a CYP3A inhibitor (see Appendix G) can be included (with an adjusted dose of zanubrutinib).
• Requiring ongoing treatment with systemic corticosteroids for an indication other than AIHA/CAD at a dose of \> 10 mg prednisone per day.
• Previous CAD treatment within the following time frames:
• Clinically significant cardiovascular disease including one of the following:
• Myocardial infarction within 6 months before screening
• Unstable angina within 3 months before screening

Sponsors & Collaborators

• Stichting Hemato-Oncologie voor Volwassenen Nederland: lead

Study Sites (10)

UZ leuven

Leuven, Belgium

Location

AZ Delta

Roeselare, Belgium

Location

Rigshospitalet

Copenhagen, Denmark

Location

Odense University Hospital

Odense, Denmark

Location

Amsterdan UMC ( location AMC)

Amsterdam, Netherlands

Location

UMCG

Groningen, Netherlands

Location

Erasusmc

Rotterdam, Netherlands

Location

Haukeland University Hospital Bergen

Bergen, Norway

Location

Oslo University Hospital

Oslo, Norway

Location

st. Olavs Hospital

Trondheim, Norway

Location

Related Links

• HOVON website

MeSH Terms

Conditions

Lymphoma

Interventions

zanubrutinib

Condition Hierarchy (Ancestors)

Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 12, 2023
• First Posted: October 4, 2023
• Study Start: July 26, 2024
• Primary Completion: February 10, 2026
• Study Completion (Estimated): November 1, 2028
• Last Updated: March 6, 2026

Record last verified: 2025-08

Locations

NO (3); NL (3); BE (2); DK (2)