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

NCT ID: NCT05735834

Last Updated: 2026-01-15

Basic Information

• Recruitment Status: ACTIVE_NOT_RECRUITING
• Clinical Phase: PHASE3
• Total Enrollment: 122 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2024-05-21
• Study Completion Date: 2029-05-31

Brief Summary

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.

Detailed Description

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.

Conditions

Splenic Marginal Zone Lymphoma

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Arm A - Rituximab + Zanubrutinib

Zanubrutinib (160 mg BID orally continuous dosing) is administered for 12 cycles of 28 days each. After cycle 12:

1. Patients in Complete Response (CR) will stop treatment and enter the follow-up phase.

2. Patients in partial response (PR) will continue zanubrutinib treatment (160 mg BID orally continuous dosing) for 12 additional cycles of 28 days each for a total of 24 cycles.

3. Patients in stable disease (SD) or progressive disease (PD) will stop treatment and will enter the follow-up phase.

Rituximab is infused at the dose of 375 mg/m2 iv on days 1, 8, 15, and 22 of cycle 1 (28 days per cycle), then on day 1 of cycles 3, 6, 9, and 12 (28 days per cycle). After cycle 12:

1. Patients in CR will stop treatment and enter the follow-up phase.

2. Patients in PR will go on with rituximab 375 mg/m2 IV on day 1 of cycles 15, 18, 21, and 24 (28 days per cycle).

3. Patients in SD or PD will discontinue treatment and will enter the follow-up phase.

Group Type: EXPERIMENTAL

Rituximab

Intervention Type: DRUG

Truxima concentrate for solution for infusion 500 mg/50 ml

Zanubrutinib

Intervention Type: DRUG

Zanubrutinib 80 mg hard capsules

Arm B - Rituximab

Rituximab is infused at the dose of 375 mg/m2 iv on days 1, 8, 15, and 22 of cycle 1 (28 days per cycle), then on day 1 of cycles 3, 6, 9, and 12 (28 days per cycle). After cycle 12:

1. Patients in CR will stop treatment and enter the follow-up phase.

2. Patients in PR will go on with rituximab 375 mg/m2 iv on day 1 of cycles 15, 18, 21, and 24 (28 days per cycle).

3. Patients in SD or PD will discontinue treatment and will enter the follow-up phase

Group Type: ACTIVE_COMPARATOR

Rituximab

Intervention Type: DRUG

Truxima concentrate for solution for infusion 500 mg/50 ml

Interventions

Rituximab

Truxima concentrate for solution for infusion 500 mg/50 ml

Intervention Type: DRUG

Zanubrutinib

Zanubrutinib 80 mg hard capsules

Intervention Type: DRUG

Other Intervention Names

Truxima; Brukinsa

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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

International Extranodal Lymphoma Study Group (IELSG)

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Davide Rossi, MD

Role: STUDY_CHAIR

Oncology Institute of Southern Switzerland - Bellinzona (Switzerland)

Emanuele Zucca, MD

Role: STUDY_CHAIR

International Extranodal Lymphoma Study Group (IELSG) - Bellinzona (Switzerland)

Luca Arcaini, MD

Role: STUDY_CHAIR

Fondazione IRCCS Policlinico San Matteo, Pavia, Italy

Locations

Medical University of Vienna

Vienna, , Austria

Institut Bergonié

Bordeaux, , France

CHU de Grenoble

Grenoble, , France

Hôpital Saint Louis

Paris, , France

Hôpital Lyon-Sud

Pierre-Bénite, , France

CHRU Nancy Brabois

Vandœuvre-lès-Nancy, , France

IRCCS Istituto Tumori Giovanni Paolo II

Bari, , Italy

IRCCS AOU di Bologna

Bologna, , Italy

ASST Spedali Civili di Brescia

Brescia, , Italy

A.O.U. Policlinico G. Rodolico-S. Marco

Catania, , Italy

IRCCS IRST Istituto Romagnolo per lo Studio dei Tumori "Dino Amadori"

Meldola, , Italy

Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico

Milan, , Italy

IRCCS Ospedale San Raffaele

Milan, , Italy

ASST Grande Ospedale Metropolitano Niguarda

Milan, , Italy

Azienda Ospedaliero Universitaria Maggiore della Carità

Novara, , Italy

Azienda Ospedaliera Ospedali Riuniti Villa Sofia Cervello

Palermo, , Italy

IRCCS Policlinico San Matteo

Pavia, , Italy

Ospedale Santa Maria delle Croci

Ravenna, , Italy

USL-IRCCS of Reggio Emilia, Arcispedale Santa Maria Nuova

Reggio Emilia, , Italy

Policlinico Santa Maria alle Scotte

Siena, , Italy

Ospedale di Circolo e Fondazione Macchi - ASST dei Sette Laghi

Varese, , Italy

Oslo University Hospital

Oslo, , Norway

St Olavs Hospital

Trondheim, , Norway

Hospedal Clinic de Barcelona

Barcelona, , Spain

Hospital del Mar

Barcelona, , Spain

Hospital Vall d'Hebron

Barcelona, , Spain

Istitut Català d'Oncologia, Hospital Duran i Reynals

Barcelona, , Spain

Hospital Universitario Cruces

Bilbao, , Spain

Hospital Virgen Arrixaca

El Palmar, , Spain

Clinica Universidad de Navarra

Madrid, , Spain

Hospital 12 De Octubre

Madrid, , Spain

Hospital Gregorio Marañón

Madrid, , Spain

Hospital Ramon y Cajal

Madrid, , Spain

Clinica Universidad de Navarra

Pamplona, , Spain

Hospital De Salamanca

Salamanca, , Spain

Hospital De Donostia

San Sebastián, , Spain

Hospital Clinico De Valencia

Valencia, , Spain

Hospital Universitario Miguel Servet

Zaragoza, , Spain

Karolinska University Hospital

Stockholm, , Sweden

Oncology Institute of Southern Switzerland

Bellinzona, , Switzerland

INSELSPITAL, Bern University Hospital

Bern, , Switzerland

University Hospitals Dorset

Bournemouth, , United Kingdom

University Hospital of Wales

Cardiff, , United Kingdom

Hospital Beatson West of Scotland Cancer Centre

Glasgow, , United Kingdom

Leicester Royal Infirmary

Leicester, , United Kingdom

Clatterbridge Cancer Centre

Liverpool, , United Kingdom

University College London Hospitals

London, , United Kingdom

Guy's Hospital - Guy's and St. Thomas' NHS Foundation Trust

London, , United Kingdom

The Christie

Manchester, , United Kingdom

Churchill Hospital

Oxford, , United Kingdom

The Royal Marsden NHS Foundation Trust

Sutton, , United Kingdom

Countries

Austria; France; Italy; Norway; Spain; Sweden; Switzerland; United Kingdom

Other Identifiers

2023-503755-10-00

Identifier Type: REGISTRY

Identifier Source: secondary_id

IELSG48

Identifier Type: -

Identifier Source: org_study_id