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

NCT05735834 | Active Not Recruiting Phase 3 DMC

• 2 other identifiers: IELSG482023-503755-10-00
• Study Type: interventional
• Target: 122
• Locations: 8 countries
• Sites: 50

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.

Conditions

Splenic Marginal Zone Lymphoma

Outcome Measures

Primary Outcomes (1)

• Progression Free Survival (PFS) rate at 3 years

  PFS is defined as the time from the date of randomization until progression (assessed by the investigator per Lugano 2014 criteria) or death from any cause, whichever occurs first

  From the date of randomization to the date of progression or the date of death from any cause until 3 years after randomization

Secondary Outcomes (8)

• Complete remission rates - Lugano 2014 criteria

  At 12 and 24 months after treatment start

• Best response

  From date of treatment start until 24 months after treatment start

• Complete remission rates - Matutes criteria

  At 12 and 24 months after treatment start

• Best response - Matutes criteria

  From date of treatment start until 24 months after treatment start

• Time to next anti-lymphoma treatment (TTNT)

  From the end of treatment to the start of the next anti-lymphoma therapy until 3 years after randomization

Study Arms (2)

Arm A - Rituximab + Zanubrutinib

EXPERIMENTAL

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.

Drug: Rituximab; Drug: Zanubrutinib

Arm B - Rituximab

ACTIVE COMPARATOR

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

Drug: Rituximab

Interventions

Rituximab DRUG

Truxima concentrate for solution for infusion 500 mg/50 ml

Also known as: Truxima

Arm A - Rituximab + Zanubrutinib; Arm B - Rituximab

Zanubrutinib DRUG

Zanubrutinib 80 mg hard capsules

Also known as: Brukinsa

Arm A - Rituximab + Zanubrutinib

Eligibility Criteria

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

You may qualify if:

• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• International Extranodal Lymphoma Study Group (IELSG): lead

Study Sites (50)

Medical University of Vienna

Vienna, Austria

Location

Institut Bergonié

Bordeaux, 33076, France

Location

CHU de Grenoble

Grenoble, 38043, France

Location

Hôpital Saint Louis

Paris, 75475, France

Location

Hôpital Lyon-Sud

Pierre-Bénite, 69495, France

Location

CHRU Nancy Brabois

Vandœuvre-lès-Nancy, 54511, France

Location

IRCCS Istituto Tumori Giovanni Paolo II

Bari, 70124, Italy

Location

IRCCS AOU di Bologna

Bologna, 40138, Italy

Location

ASST Spedali Civili di Brescia

Brescia, 25123, Italy

Location

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

Catania, 95123, Italy

Location

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

Meldola, 47014, Italy

Location

Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico

Milan, 20122, Italy

Location

IRCCS Ospedale San Raffaele

Milan, 20132, Italy

Location

ASST Grande Ospedale Metropolitano Niguarda

Milan, 20162, Italy

Location

Azienda Ospedaliero Universitaria Maggiore della Carità

Novara, 28100, Italy

Location

Azienda Ospedaliera Ospedali Riuniti Villa Sofia Cervello

Palermo, 90146, Italy

Location

IRCCS Policlinico San Matteo

Pavia, Italy

Location

Ospedale Santa Maria delle Croci

Ravenna, 48121, Italy

Location

USL-IRCCS of Reggio Emilia, Arcispedale Santa Maria Nuova

Reggio Emilia, 42123, Italy

Location

Policlinico Santa Maria alle Scotte

Siena, 53100, Italy

Location

Ospedale di Circolo e Fondazione Macchi - ASST dei Sette Laghi

Varese, 21100, Italy

Location

Oslo University Hospital

Oslo, Norway

Location

St Olavs Hospital

Trondheim, Norway

Location

Hospedal Clinic de Barcelona

Barcelona, Spain

Location

Hospital del Mar

Barcelona, Spain

Location

Hospital Vall d'Hebron

Barcelona, Spain

Location

Istitut Català d'Oncologia, Hospital Duran i Reynals

Barcelona, Spain

Location

Hospital Universitario Cruces

Bilbao, Spain

Location

Hospital Virgen Arrixaca

El Palmar, Spain

Location

Clinica Universidad de Navarra

Madrid, Spain

Location

Hospital 12 De Octubre

Madrid, Spain

Location

Hospital Gregorio Marañón

Madrid, Spain

Location

Hospital Ramon y Cajal

Madrid, Spain

Location

Clinica Universidad de Navarra

Pamplona, Spain

Location

Hospital De Salamanca

Salamanca, Spain

Location

Hospital De Donostia

San Sebastián, Spain

Location

Hospital Clinico De Valencia

Valencia, Spain

Location

Hospital Universitario Miguel Servet

Zaragoza, Spain

Location

Karolinska University Hospital

Stockholm, Sweden

Location

Oncology Institute of Southern Switzerland

Bellinzona, 6500, Switzerland

Location

INSELSPITAL, Bern University Hospital

Bern, 3010, Switzerland

Location

University Hospitals Dorset

Bournemouth, BH7 7DW, United Kingdom

Location

University Hospital of Wales

Cardiff, CF14 4XW, United Kingdom

Location

Hospital Beatson West of Scotland Cancer Centre

Glasgow, G12 0YN, United Kingdom

Location

Clatterbridge Cancer Centre

Liverpool, L7 8YA, United Kingdom

Location

University College London Hospitals

London, NW1 2PG, United Kingdom

Location

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

London, SE1 9RT, United Kingdom

Location

The Christie

Manchester, M20 4BX, United Kingdom

Location

Churchill Hospital

Oxford, OX3 7LE, United Kingdom

Location

The Royal Marsden NHS Foundation Trust

Sutton, SM2 5PT, United Kingdom

Location

MeSH Terms

Interventions

Rituximab; zanubrutinib

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Murine-Derived; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• Davide Rossi, MD

  Oncology Institute of Southern Switzerland - Bellinzona (Switzerland)

  STUDY CHAIR

• Emanuele Zucca, MD

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

  STUDY CHAIR

• Luca Arcaini, MD

  Fondazione IRCCS Policlinico San Matteo, Pavia, Italy

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 9, 2023
• First Posted: February 21, 2023
• Study Start: May 21, 2024
• Primary Completion (Estimated): May 1, 2029
• Study Completion (Estimated): May 1, 2029
• Last Updated: April 1, 2026

Record last verified: 2026-03

Locations

NO (2); SE (1); IT (15); GB (9); ES (15); CH (2); AU (1); FR (5)