Clinical trial NCT05735834: Comparison Between Rituximab Plus Zanubrutinib Versus Rituximab Monotherapy in Untreated SMZL Patients
Official title: Phase 3, Interventional, Multicentre, Open-label, Randomized Study Comparing Rituximab Plus Zanubrutinib to Rituximab Monotherapy in Previously Untreated, Symptomatic Splenic Marginal Zone Lymphoma (RITZ)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Splenic Marginal Zone Lymphoma
Lead sponsor: International Extranodal Lymphoma Study Group (IELSG)
Sponsor class: OTHER
First posted: 2023-02-21
Enrollment: 120
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Progression Free Survival (PFS) rate at 3 years
timeFrame: 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:
measure: Complete remission rates - Lugano 2014 criteria
timeFrame: At 12 and 24 months after treatment start
measure: Best response
timeFrame: From date of treatment start until 24 months after treatment start
measure: Complete remission rates - Matutes criteria
timeFrame: At 12 and 24 months after treatment start
measure: Best response - Matutes criteria
timeFrame: From date of treatment start until 24 months after treatment start
measure: Time to next anti-lymphoma treatment (TTNT)
timeFrame: From the end of treatment to the start of the next anti-lymphoma therapy until 3 years after randomization
measure: Duration of response (DoR)
timeFrame: From the time when criteria for response (ie, CR or PR) are met to the first documentation of relapse or progression until 3 years from randomization
measure: Overall Survival (OS)
timeFrame: From the time of randomization until death as a result of any cause until 3 years from randomization
measure: Treatment Emergent Adverse Events (AEs)
timeFrame: From the time of ICF signature until 28 days after treatment discontinuation or until resolution of all treatment-related AEs, whichever occurs later, or starting of a new anti-neoplastic treatment up to 3 years from randomization
Other outcomes:
Locations:
city: Vienna
country: Austria
facility: Medical University of Vienna
city: Aarhus
country: Denmark
facility: Aarhus University Hospital
city: Bordeaux
country: France
facility: Institut Bergonié
city: Grenoble
country: France
facility: CHU de Grenoble
city: Paris
country: France
facility: Hôpital Saint Louis
city: Pierre-Bénite
country: France
facility: Hôpital Lyon-Sud
city: Vandœuvre-lès-Nancy
country: France
facility: CHRU Nancy Brabois
city: Bari
country: Italy
facility: IRCCS Istituto Tumori Giovanni Paolo II
city: Bologna
country: Italy
facility: IRCCS AOU di Bologna
city: Brescia
country: Italy
facility: ASST Spedali Civili di Brescia
city: Catania
country: Italy
facility: A.O.U. Policlinico G. Rodolico-S. Marco
city: Meldola
country: Italy
facility: IRCCS IRST Istituto Romagnolo per lo Studio dei Tumori "Dino Amadori"
city: Milan
country: Italy
facility: Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico
city: Milan
country: Italy
facility: IRCCS Ospedale San Raffaele
city: Milan
country: Italy
facility: ASST Grande Ospedale Metropolitano Niguarda
city: Novara
country: Italy
facility: Azienda Ospedaliero Universitaria Maggiore della Carità
city: Palermo
country: Italy
facility: Azienda Ospedaliera Ospedali Riuniti Villa Sofia Cervello
city: Pavia
country: Italy
facility: IRCCS Policlinico San Matteo
city: Ravenna
country: Italy
facility: Ospedale Santa Maria delle Croci
city: Reggio Emilia
country: Italy
facility: USL-IRCCS of Reggio Emilia, Arcispedale Santa Maria Nuova
city: Siena
country: Italy
facility: Policlinico Santa Maria alle Scotte
city: Varese
country: Italy
facility: Ospedale di Circolo e Fondazione Macchi - ASST dei Sette Laghi
city: Oslo
country: Norway
facility: Oslo University Hospital
city: Trondheim
country: Norway
facility: St Olavs Hospital
city: Barcelona
country: Spain
facility: Hospedal Clinic de Barcelona
city: Barcelona
country: Spain
facility: Hospital del Mar
city: Barcelona
country: Spain
facility: Hospital Vall d'Hebron
city: Barcelona
country: Spain
facility: Istitut Català d'Oncologia, Hospital Duran i Reynals
city: Bilbao
country: Spain
facility: Hospital Universitario Cruces
city: El Palmar
country: Spain
facility: Hospital Virgen Arrixaca
city: Madrid
country: Spain
facility: Clinica Universidad de Navarra
city: Madrid
country: Spain
facility: Hospital 12 De Octubre
city: Madrid
country: Spain
facility: Hospital Gregorio Marañón
city: Madrid
country: Spain
facility: Hospital Ramon y Cajal
city: Pamplona
country: Spain
facility: Clinica Universidad de Navarra
city: Salamanca
country: Spain
facility: Hospital De Salamanca
city: San Sebastián
country: Spain
facility: Hospital De Donostia
city: Valencia
country: Spain
facility: Hospital Clinico De Valencia
city: Zaragoza
country: Spain
facility: Hospital Universitario Miguel Servet
city: Stockholm
country: Sweden
facility: Karolinska University Hospital
city: Bellinzona
country: Switzerland
facility: Oncology Institute of Southern Switzerland
city: Bern
country: Switzerland
facility: INSELSPITAL, Bern University Hospital
city: Birmingham
country: United Kingdom
facility: Birmingham Hearthland Hospital
city: Bournemouth
country: United Kingdom
facility: University Hospitals Dorset
city: Cardiff
country: United Kingdom
facility: University Hospital of Wales
city: Glasgow
country: United Kingdom
facility: Hospital Beatson West of Scotland Cancer Centre
city: Leicester
country: United Kingdom
facility: Leicester Royal Infirmary
city: Liverpool
country: United Kingdom
facility: Clatterbridge Cancer Centre
city: London
country: United Kingdom
facility: University College London Hospitals
city: London
country: United Kingdom
facility: Guy's Hospital - Guy's and St. Thomas' NHS Foundation Trust
city: Manchester
country: United Kingdom
facility: The Christie
city: Oxford
country: United Kingdom
facility: Churchill Hospital
city: Plymouth
country: United Kingdom
facility: Derriford Hospital
city: Southampton
country: United Kingdom
facility: University Hospitals Southampton
city: Sutton
country: United Kingdom
facility: The Royal Marsden NHS Foundation Trust
Study officials:
affiliation: Oncology Institute of Southern Switzerland - Bellinzona (Switzerland)
name: Davide Rossi, MD
role: STUDY_CHAIR
affiliation: International Extranodal Lymphoma Study Group (IELSG) - Bellinzona (Switzerland)
name: Emanuele Zucca, MD
role: STUDY_CHAIR
affiliation: Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
name: Luca Arcaini, MD
role: STUDY_CHAIR
References: