ZANUBRUTINIB for Cold agglutinin disease

Inclusion criteria

• {"criterion_text":"- CAD diagnosis defined by the combination of: a. Chronic hemolysis (>3 months; suppressed haptoglobin) and b. Cold agglutinin titer of 64 or higher at 4°C and c. Positive direct antiglobulin test, strongly positive (at least 2+) with anti-C3d and negative or weakly positive (maximum 1+) with anti-IgG, AND: The presence of a clonal B-cell lymphoproliferative disorder defined by: a. M-protein by serum electrophoresis confirmed by immunofixation, and/or b. A clonal CD20 positive lymphocyte population in the bone marrow (a very small clone visible only by flow cytometry is allowed)\n- Written informed consent.\n- Patient is capable of giving informed consent and can understand and agree to comply with the requirements of the study and the schedule.\n- Indication for therapy: Hb ≤ 10.5 g/dL AND/OR Considerable cold induced peripheral symptoms (grade 2 or more; see appendix E)\n- 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.\n- Age ≥ 18 years.\n- ECOG/WHO performance status ≤ 2 (see appendix B). WHO performance status 3 is allowed if related to the CAD.\n- Adequate bone marrow function as defined by: Absolute neutrophil count (ANC) > 1.0 × 109/L and Platelets ≥ 100 x109/L\n- 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.\n- Applicable only if the indication for treatment (as indicated above) is Hb ≤ 10.5 g/dL: presence of a measurable parameter for hemolysis, EITHER total bilirubin level above the upper limit of normal (ULN), not attributable to Gilbert's syndrome, AND/OR LDH level above the ULN.  Applicable only if the indications for treatment (as indicated above) is CIPS: Total bilirubin level and LDH may be above the upper limit of normal (ULN), but normal values are accepted\n- Negative pregnancy test at study entry for woman of childbearing potential.\n- 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.\n- 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."}

Exclusion criteria

• {"criterion_text":"- A diagnosis of aggressive 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.)\n- Uncontrolled HIV infection. Patients with HIV positivity but controlled infection (= sustained negative viral load) may be enrolled.\n- 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.\n- 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).\n- Presence of Hepatitis C (HCV) antibody.\n- Active fungal, bacterial and/or viral infection requiring systemic therapy.\n- Vaccination with a live vaccine within 28 days prior to the first dose of study drug.\n- Pregnant or breastfeeding women.\n- Current participation in another interventional clinical trial.\n- 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.\n- History of intolerance to the active ingredients or other ingredients of zanubrutinib.\n- Cold agglutinin syndrome (CAS) secondary to specific infection (Mycoplasma or Epstein-Barr virus) or rheumatological disorders\n- Requiring ongoing treatment with systemic corticosteroids for an indication other than AIHA/CAD at a dose of > 10 mg prednisone per day.\n- 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.\n- 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); 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.\n- Severe or debilitating pulmonary disease (CTCAE grade III-IV, see appendix D).\n- 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.\n- 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).\n- Significant hepatic dysfunction (transaminases ≥ 2.5 times ULN and/or serum direct bilirubin ≥ 2 x ULN).\n- Known active or latent mycobacterial infection.\n- Mixed AIHA, Evans syndrome (concurrent autoimmune thrombocytopenia/ITP).\n- 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.\n- 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.\n- History of stroke or intracranial hemorrhage within 6 months before first dose of study drug.\n- Previous treatment with BTKi.\n- Major surgery within 4 weeks of the first dose of study drug.\n- 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."}

Primary endpoints

• {"endpoint_text":"- CAD response rate (PR or CR) after 6 cycles of zanubrutinib treatment. Time of primary outcome assessment: at the end of cycle 6 (day 22-28) before starting cycle 7.","definition_or_measurement_approach":"CAD response rate defined as PR or CR after 6 cycles; primary outcome assessed at end of cycle 6 (day 22-28) prior to cycle 7."}

Secondary endpoints

• {"endpoint_text":"- Rate of CAD response categories (CR, PR or none; separately) after 6 cycles of treatment and best CAD response on protocol\n- Time to CAD response, time to best CAD response and duration of CAD response.\n- Hematological response after 6 cycles, best hematological response on protocol, time to hematological response and time to best hematological response and duration of hematological response.\n- 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.\n- Percentage of patients with cold-induced symptoms at baseline that achieve improvement or resolution of these symptoms after 6 cycles and overall on protocol.\n- Time for patients with cold-induced symptoms at baseline to achieve improvement or resolution of these symptoms.\n- Time to transfusion independence (in patients that are transfusion dependent at baseline).\n- Progression free survival at 6 months and 3 years, defined as time from registration to relapse of CAD or death from any cause, whichever comes first.\n- Overall survival at 3 years, defined as time from registration to death from any cause.\n- Toxicity as defined by type,frequency and severity of adverse events according to the NCI Common Terminology Criteria for Adverse Events version 5.0.\n- Impact of zanubrutinib treatment on Quality of life and Fatigue measured as patient-reported outcomes (FACIT-Fatigue and EQ5D-5L questionnaires)","definition_or_measurement_approach":"Endpoints measured per protocol definitions: CAD response categories (CR/PR/none) after 6 cycles; time-to-event endpoints defined from registration; hematological and biomarker measurements compared to baseline; toxicity per NCI CTCAE v5.0; QoL via FACIT-Fatigue and EQ5D-5L questionnaires."}

Netherlands

Earliest CTIS Part Ii Submission Date

12-03-2024

Latest Decision Or Authorization Date

18-07-2025

Processing Time Days

493

Number Of Sites

3

Number Of Participants

13

Belgium

Earliest CTIS Part Ii Submission Date

12-03-2024

Latest Decision Or Authorization Date

15-07-2025

Processing Time Days

490

Number Of Sites

2

Number Of Participants

5

Denmark

Earliest CTIS Part Ii Submission Date

12-03-2024

Latest Decision Or Authorization Date

15-07-2025

Processing Time Days

490

Number Of Sites

2

Number Of Participants

3

Norway

Earliest CTIS Part Ii Submission Date

12-03-2024

Latest Decision Or Authorization Date

15-07-2025

Processing Time Days

490

Number Of Sites

2

Number Of Participants

5

Primary sponsor

Full Name

Haemato Oncology Foundation For Adults Netherlands

Organisation Type

Hospital/Clinic/Other health care facility

Country Of Registered Address

Netherlands

Third parties

• {"country":"Norway","full_name":"Oslo University Hospital HF","duties_or_roles":"1","organisation_type":"Hospital/Clinic/Other health care facility"}
• {"country":"Netherlands","full_name":"Sanquin Diagnostiek B.V.","duties_or_roles":"4","organisation_type":"Laboratory/Research/Testing facility"}
• {"country":"Denmark","full_name":"Frederiksberg Hospital","duties_or_roles":"1","organisation_type":"Hospital/Clinic/Other health care facility"}
• {"country":"Norway","full_name":"University Of Oslo","duties_or_roles":"4","organisation_type":"Educational Institution"}
• {"country":"Belgium","full_name":"Clinigen Clinical Supplies Management","duties_or_roles":"14","organisation_type":"Pharmaceutical company"}
• {"country":"Netherlands","full_name":"Amsterdam UMC","duties_or_roles":"15|Biobanking","organisation_type":"Hospital/Clinic/Other health care facility"}