Comparison Between Rituximab Plus Zanubrutinib Versus Rituximab Monotherapy in Untreated SMZL Patients

The goal of this clinical trial is to compare the efficacy and tolerability of the combination of two medicinal products, rituximab, and zanubrutinib, compared to rituximab monotherapy in patients with Splenic Marginal Zone Lymphoma (SMZL), previously untreated and who need systemic treatment.

The main questions it aims to answer are:

* Is the combination rituximab and zanubrutinib a more effective therapy than rituximab monotherapy?
* Is the combination therapy, rituximab and zanubrutinib, well tolerated?

Study participants will be put into one of the two treatment groups (rituximab and zanubrutinib or rituximab alone) for a maximum of two years and will undergo regular visits until three years from treatment start.

Phase III, interventional, multicenter, open label, randomized study to evaluate whether treatment with zanubrutinib in combination with rituximab will result in an improvement in Progression Free Survival (PFS) compared to treatment with rituximab in patients with previously untreated splenic marginal zone lymphoma (SMZL).

Approximately 120 subjects will be randomized in a 1:1 ratio to receive zanubrutinib and rituximab (Treatment Arm A) or rituximab (Treatment Arm B). The study will include a Screening Phase, a Treatment Phase, and a Follow-Up Phase.

Subjects with investigator-confirmed progressive disease (PD) according to the Lugano 2014 criteria or unacceptable toxicity, or investigator/subject decision must discontinue study treatment.

Patients who complete the treatment and patients who will discontinue treatment for any reason will enter the Follow-up Phase.

The Response Follow-up Phase will occur for subjects who complete the treatment or discontinue for reasons other than disease progression and will include efficacy assessments every 24 weeks until investigator-assessed disease progression.

Subjects with PD during the Response Follow-up Phase will continue to be followed in the Survival Follow-up Phase.

An Independent Data Monitoring Committee (IDMC) will be responsible for independent review of the interim safety analysis on the first 20 enrolled patients in the experimental arm.

Eligibility Criteria:
Inclusion Criteria:

* Ability to understand and willingness to sign a written informed consent in accordance with ICH/GCP regulations before registration and prior to any trial-specific procedures.
* Confirmed diagnosis of SMZL, including Matutes immunophenotype score \<3. Evaluation of the following features is desirable: absence of CD103 expression by flow cytometry, absence of Cyclin D1, BCL6, and CD10 expression by immunohistochemistry, and absence of the MYD88 L265P mutation. Patients with prominent splenomegaly and involvement of the splenic hilar and/or extra hilar lymph nodes are eligible
* Previously untreated disease. Patients with prior hepatitis C virus (HCV) infection who underwent HCV eradication and have persistent SMZL after 3 months post-eradication can be included.
* Treatment needs according to the ESMO guideline criteria
* Measurable lesions
* Age ≥ 18 years.
* European Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2.
* Absolute neutrophil count (ANC) ≥ 1.0 x 109/L, platelet count ≥ 50 x 109/L, Hb \> 7.5 g/dl. Values below such thresholds are allowed if attributable to the underlying lymphoma. Transfusions are allowed if clinically indicated during screening.
* Adequate hepatic and renal function and coagulation parameters
* Patient able and willing to swallow trial drugs as whole tablet/capsule

Exclusion Criteria:

* Previous splenectomy.
* Any systemic therapy for SMZL.
* Patients with central nervous system (CNS) involvement.
* Prior malignancy (other than the disease under study) within the past 2 years, except for curatively treated basal or squamous skin cancer, superficial bladder cancer, carcinoma in situ of the cervix or breast, or localized Gleason score ≤ 6 prostate cancer.
* Clinically significant cardiovascular disease
* History of cerebrovascular accident or intracranial hemorrhage within 6 months before registration and known bleeding disorders (eg, von Willebrand's disease or hemophilia).
* History of confirmed progressive multifocal leukoencephalopathy (PML).
* Concomitant diseases that require anticoagulant therapy with warfarin or phenprocoumon or other vitamin K antagonists and patients treated with dual anti-platelet therapy. Patients being treated with factor Xa inhibitors (eg, rivaroxaban, apixaban, edoxaban), direct thrombin inhibitors (e. dabigatran) low molecular weight heparin (LMWH), or single anti-platelet agents (eg. aspirin, clopidogrel) can be included but must be properly informed about the potential risk of bleeding.
* Malabsorption syndrome or other condition that precludes the enteral route of administration.
* Any uncontrolled active systemic infection requiring intravenous antimicrobial treatment.
* Known human immunodeficiency virus (HIV) infection.
* Active COronaVIrus Disease 19 (COVID-19) infection or non-compliance with the prevailing hygiene measures regarding the COVID-19 pandemic.
* Active chronic hepatitis C or hepatitis B virus infection
* Active, uncontrolled autoimmune phenomenon (autoimmune hemolytic anemia or immune. thrombocytopenia) requiring steroid therapy with \> 20 mg daily of prednisone dose or equivalent.
* Known hypersensitivity to trial drugs or any component of the trial drugs.
* Concomitant treatment with strong CYP3A inducers or inhibitors
* Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that in the opinion of the investigator may increase the risk associated with trial participation or investigational product administration or may interfere with the interpretation of trial results and/or would make the patient inappropriate for enrolment into this trial.
* Pregnancy or breastfeeding.
* Concurrent participation in another therapeutic clinical trial.