LymphomaPhase 2HOVON169CADNCT06067048
Zanubrutinib in Primary Cold Agglutinin Disease
A Phase 2 study testing Zanubrutinib Oral Capsule in people with Lymphoma, run by Stichting Hemato-Oncologie voor Volwassenen Nederland at 10 sites in 4 countries.
Trial 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). Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Lymphoma
- What is being tested?
- Zanubrutinib Oral Capsule
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 25 participants
- Where
- 10 sitesin 4 countries
- Study dates
- 26 Jul 2024to 1 Nov 2028
- Phase
- Phase 2
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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:
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- 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.
- ECOG/WHO performance status ≤ 2 (see appendix B). WHO performance status 3 is allowed if related to the CAD.
- Adequate bone marrow function as defined by:
- Absolute neutrophil count (ANC) > 1.0 × 109/L, and
- Platelets ≥ 100 x109/L.
- Ferritin levels above the lower limit of normal (LLN). Concurrent treatment with iron supplementation is permitted if the patient has been on a stable dose during the previous 4 weeks.
- Total bilirubin level above the upper limit of normal (ULN), as a measurable parameter for hemolysis, and that is not attributable to Gilbert's syndrome.
- Negative pregnancy test at study entry for woman of childbearing potential.
- Women of childbearing potential must be: (1) surgically sterile or ≥ 2 years after the onset of menopause; (2) willing to use a highly effective contraceptive method such as oral contraceptives, intrauterine device, or sexual abstinence during study treatment and for ≥ 90 days after last dose of zanubrutinib.
- Male patients with a female partner of childbearing potential are eligible if vasectomized or if they agree to the use of barrier contraception with other methods as described above during the study treatment period and for ≥ 90 days after the last dose of zanubrutinib.
- Written informed consent.
- Patient is capable of giving informed consent and can understand and agrees to comply with the requirements of the study and the schedule.
Who cannot join
- A patient who meets any of the following criteria cannot be included in this study:
- A diagnosis of agressive lymphoma, chronic lymphocytic leukemia (CLL), or the presence of overt extramedullary B-cell lymphoproliferative disease. (Note: presence of a B-cell lymphoproliferative disorder, limited to the bone marrow, including WM, MZL or IgM MGUS, is allowed. However, the indication for treatment should be only cold agglutinin-related, as per inclusion criteria.)
- 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.
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- 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:
- rituximab, or bortezomib monotherapy within 3 months prior to inclusion
- bendamustine, fludarabine or other cytotoxic therapy with or without rituximab, or bortezomib with rituximab, within 4 months prior to inclusion
- anticomplement therapies within 5 half-lives of the specific drug prior to inclusion
- Erythropoietin use, which has not been at a stable dose within 3 months prior to inclusion
- Clinically significant cardiovascular disease including one of the following:
- Myocardial infarction within 6 months before screening
- Unstable angina within 3 months before screening
- New York Heart Association (NYHA) class III or IV congestive heart failure (see appendix D)
- d History of clinically significant arrhythmias (eg, sustained ventricular tachycardia, ventricular fibrillation, torsades de pointes)
- QTcF > 480ms based on Fridericia's formula
- History of Mobitz II second-degree or third-degree heart block without a permanent pacemaker in place
- Uncontrolled hypertension as indicated by a minimum of 2 consecutive blood pressure measurements showing systolic blood pressure > 170 mmHg and diastolic blood pressure > 105 mmHg at screening
- Severe or debilitating pulmonary disease (CTCAE grade III-IV, see appendix D).
- Unable to swallow capsules or disease significantly affecting gastrointestinal function such as malabsorption syndrome, resection of the stomach or small bowel, bariatric surgery procedures, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction.
- Significant renal dysfunction (creatinine clearance < 30 mL/min after rehydration as estimated by the Cockcroft-Gault equation or the Modification of Diet in Renal Disease [MDRD] equation or as measured by nuclear medicine scan or 24-hour urine collection).
- Significant hepatic dysfunction (transaminases ≥ 2.5 times ULN and/or serum direct bilirubin ≥ 2 x ULN). ( Elevated indirect (unconjugated) bilirubin is accepted if this is related to active hemolysis.
- Uncontrolled HIV infection. Patients with HIV positivity but controlled infection (= sustained negative viral load) may be enrolled.
- Known hepatitis B infection with serologic status: presence of hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb). Patients with presence of HBcAb, but absence of HBsAg, are eligible if HBV DNA is undetectable (< 20 IU/mL), and if they are willing to undergo monitoring for HBV reactivation.
- Presence of Hepatitis C (HCV) antibody.
- Active fungal, bacterial and/or viral infection requiring systemic therapy.
- Known active or latent mycobacterial infection.
- Vaccination with a live vaccine within 28 days prior to the first dose of study drug.
- Pregnant or breastfeeding women.
- Current participation in another interventional clinical trial.
- Underlying medical conditions that, in the investigator's opinion, will render the administration of study drug hazardous or obscure the interpretation of toxicity or AEs, including
- severe neurological, psychological, familial, sociological or geographical condition which would compromise ability to comply with study procedures, or is accompanied by a life expectancy of < 6 months.
- History of intolerance to the active ingredients or other ingredients of zanubrutinib.
Trial locations and contacts
10 sites in 4 countries.
10 sites in 4 countries
Netherlands3 sites
Amsterdan UMC ( location AMC)
Amsterdam
UMCG
Groningen
Erasusmc
Rotterdam
Norway3 sites
Haukeland University Hospital Bergen
Bergen
Oslo University Hospital
Oslo
st. Olavs Hospital
Trondheim
About this study
Official title: Phase II Trial of Zanubrutinib in Primary Cold Agglutinin Disease. CaZa Study
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
- Being tested
- Zanubrutinib Oral Capsule
- Medical subject headings
- Lymphoma
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Zanubrutinib Oral CapsuleDrug
Also called Brukinsa
36 cycles (1 cycle is 28 days)
| Study group | Role | What they receive |
|---|---|---|
| Treatment arm | Experimental | Zanubrutinib, 320 mg per day (four 80 mg capsules) Receives: Drug: Zanubrutinib Oral Capsule |
What is being measured
The primary outcome is the main question the study is designed to answer.
CAD response rate (PR or CR) after 6 cycles of zanubrutinib treatment
Measured: 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
Measured: 3 years
Time to CAD response and time to best CAD response.
Measured: 3 years
Hematological response rates after 6 cycles, as per the classification criteria defined by the IWWM-6.
Measured: 3 years
Best hematological response rates on protocol, as per the classification criteria defined by the IWWM-6
Measured: 3 years
Duration of CAD response and duration of hematological response
Measured: 3 years
Change in IgM, M-protein, Hb and hemolytic parameters (bilirubin, LDH) after 6 cycles compared to baseline including median change and maximal change overall on protocol
Measured: 3 years
Percentage of patients with cold-induced symptoms at baseline that achieve improvement or resolution of these symptoms after 6 cycles and overall on protocol.
Measured: 3 years
Time for patients with cold-induced symptoms at baseline to achieve improvement or resolution of these symptoms.
Measured: 3 years
Time to transfusion independence (in patients that are transfusion dependent at baseline)
Measured: 3 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted4 Oct 2023
- Study start26 Jul 2024
- Primary completion10 Feb 2026
- Study completion1 Nov 2028 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for LymphomaStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 25 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Stichting Hemato-Oncologie voor Volwassenen Nederland
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT06067048
- Sponsor's protocol ID
- HO169
- Acronym
- HOVON169CAD
- Status last verified
- Aug 2025
- First submitted
- 12 Jul 2023
- Last updated
- 6 Mar 2026
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Undecided
Study at a glance
From the registry record, last updated by the sponsor on 6 Mar 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Phase II Trial of Zanubrutinib in Primary Cold Agglutinin Disease. CaZa Study
- ClinicalTrials.gov ID
- NCT06067048
- Acronym / sponsor ID
- HOVON169CAD / HO169
- Conditions
- Lymphoma
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Active, not recruiting
- Enrolment
- 25 participants (estimated)
- Lead sponsor
- Stichting Hemato-Oncologie voor Volwassenen NederlandUniversity, hospital or other
- Study start
- 26 Jul 2024 (actual)
- Primary completion
- 10 Feb 2026 (actual)
- Study completion
- 1 Nov 2028 (estimated)
- First posted
- 4 Oct 2023 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Treatment arm | Experimental | Drug: Zanubrutinib Oral CapsuleZanubrutinib, 320 mg per day (four 80 mg capsules) |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (26 listed)
- In order to be eligible to participate in this study, a patient must meet all of the following criteria:
- 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,
- M-protein by serum electrophoresis confirmed by immunofixation, and/or
Key exclusion criteria (40 listed)
- A diagnosis of agressive lymphoma, chronic lymphocytic leukemia (CLL), or the presence of overt extramedullary B-cell lymphoproliferative disease. (Note: presence of a B-cell lymphoproliferative disorder, limited to the bone marrow, including WM, MZL or IgM MGUS, is allowed. However, the indication for treatment should be only cold agglutinin-related, as per inclusion criteria.)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Zanubrutinib Oral CapsuleAlso: Brukinsa36 cycles (1 cycle is 28 days) | Drug | Treatment arm |
Primary outcome
CAD response rate (PR or CR) after 6 cycles of zanubrutinib treatment
Time frame: 1 year
9 secondary outcomes
Rate of CAD response categories (CR, PR or none; separately) after 6 cycles of treatment and best CAD response on protocol
Time frame: 3 years
Time to CAD response and time to best CAD response.
Time frame: 3 years
Hematological response rates after 6 cycles, as per the classification criteria defined by the IWWM-6.
Time frame: 3 years
Best hematological response rates on protocol, as per the classification criteria defined by the IWWM-6
Time frame: 3 years
Duration of CAD response and duration of hematological response
Time frame: 3 years
Change in IgM, M-protein, Hb and hemolytic parameters (bilirubin, LDH) after 6 cycles compared to baseline including median change and maximal change overall on protocol
Time frame: 3 years
Percentage of patients with cold-induced symptoms at baseline that achieve improvement or resolution of these symptoms after 6 cycles and overall on protocol.
Time frame: 3 years
Time for patients with cold-induced symptoms at baseline to achieve improvement or resolution of these symptoms.
Time frame: 3 years
Time to transfusion independence (in patients that are transfusion dependent at baseline)
Time frame: 3 years
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 6 Mar 2026.
- HOVON websiteLink provided by the sponsor.
- Individual participant dataSharing planned: Undecided
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
The record lists no contact. Use the official record to reach the sponsor.
10 sites in 4 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Zanubrutinib Oral Capsule in people with Lymphoma, run by Stichting Hemato-Oncologie voor Volwassenen Nederland at 10 sites in 4 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 26 inclusion and 40 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: under way, not looking for participants, as of the sponsor's last update on 6 Mar 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 10 sites in Netherlands, Norway, Belgium, Denmark. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
CAD response rate (PR or CR) after 6 cycles of zanubrutinib treatment (time frame: 1 year). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 6 Mar 2026.