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

Splenic Marginal Zone Lymphoma Clinical Trial

— RITZ  

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)

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05735834
• Other study ID #: IELSG48
• Secondary ID: 2023-503755-10-0
• Status: Recruiting
• Phase: Phase 3
• Start date: May 21, 2024
• Est. completion date: May 2029

Study information

• Verified date: June 2024
• Source: International Extranodal Lymphoma Study Group (IELSG)
• Contact: Emanuele Zucca, MD
• Phone: +41 58 666
• Email: ielsg[@]ior.usi.ch
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 120
• Est. completion date: May 2029
• Est. primary completion date: May 2029
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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, absence of CD103 and CD25 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. Patients with previous splenectomy are excluded.

• 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.

Related Conditions & MeSH terms

• Lymphoma
• Lymphoma, B-Cell, Marginal Zone
• Splenic Marginal Zone Lymphoma

Intervention

Drug:
• Rituximab
Truxima concentrate for solution for infusion 500 mg/50 ml
• Zanubrutinib
Zanubrutinib 80 mg hard capsules

Locations

Country	Name	City	State
Denmark	Aarhus University Hospital	Aarhus
France	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
Italy	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	ASST Grande Ospedale Metropolitano Niguarda	Milan
Italy	Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico	Milan
Italy	IRCCS Ospedale San Raffaele	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 Tor Vergata	Rom
Italy	Policlinico Santa Maria alle Scotte	Siena
Italy	Ospedale di Circolo e Fondazione Macchi - ASST dei Sette Laghi	Varese
Norway	Oslo University Hospital	Oslo
Spain	Hospedal Clinic de Barcelona	Barcelona
Spain	Hospital del Mar	Barcelona
Spain	Istitut Català d'Oncologia, Hospital Duran i Reynals	Barcelona
Spain	Hospital Universitario Cruces	Bilbao
Spain	Hospital Virgen Arrixaca	El Palmar
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
Sweden	Karolinska University Hospital	Stockholm
Switzerland	Oncology Institute of Southern Switzerland	Bellinzona
Switzerland	INSELSPITAL, Bern University Hospital	Bern

Sponsors (1)

Lead Sponsor	Collaborator
International Extranodal Lymphoma Study Group (IELSG)

Countries where clinical trial is conducted

Denmark,  France,  Italy,  Norway,  Spain,  Sweden,  Switzerland, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Complete remission rates - Lugano 2014 criteria	Investigator-assessed complete remission rates achieved at 12 and 24 months of treatment, assessed according to the Lugano 2014 criteria	At 12 and 24 months after treatment start
Secondary	Best response	Investigator-assessed best response achieved at any time during the treatment period (24 months) assessed according to the Lugano 2014 criteria	From date of treatment start until 24 months after treatment start
Secondary	Complete remission rates - Matutes criteria	Investigator-assessed complete remission rates achieved at 12 and 24 months of treatment, assessed according to the Matutes criteria	At 12 and 24 months after treatment start
Secondary	Best response - Matutes criteria	Investigator-assessed best response achieved at any time during the treatment period (24 months) assessed according to the Matutes criteria	From date of treatment start until 24 months after treatment start
Secondary	Time to next anti-lymphoma treatment (TTNT)	Investigator-assessed time to next anti-lymphoma treatment (TTNT) according to the Lugano 2014 criteria. TTNT is defined as time from the end of treatment until the start of the next therapy	From the end of treatment to the start of the next anti-lymphoma therapy until 3 years after randomization
Secondary	Duration of response (DoR)	Investigator-assessed DoR according to the Lugano 2014 criteria	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
Secondary	Overall Survival (OS)	OS according to the Lugano 2014 criteria. OS is defined as the time from random assignment until death as a result of any cause	From the time of randomization until death as a result of any cause until 3 years from randomization
Secondary	Treatment Emergent Adverse Events (AEs)	Analysis of type and severity of adverse events (AEs) according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) v5.0	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