Mosunetuzumab and Zanubrutinib in Relapsed/Refractory Follicular Lymphoma Patients (MOZART): A Phase II, Chemo-Free Trial from Fondazione Italiana Linfomi (FIL)

Background and significance

The treatment of R/R FL is shifting toward novel and tailored chemo-free approaches. Zanubrutinib (Z) has shown marked anti-lymphoma activity when used in combination with immunotherapy paving the way for new combination strategies as shown by the ROSEWOOD trial where the combination of Z and obinutuzumab (O), (ZO), was found to be effective with a favorable benefit-risk profile (Zinzani, JCO 2023). Therefore, Z might represent an ideal drug to combine with T-cell engagers due to low toxicity and potential synergistic effects. The bispecific antibody mosunetuzumab (M) is the most extensively studied in FL, showing deep and durable remissions with favorable safety profile as monotherapy and in combination in highly pre-treated FL patients (Budde, The Lancet Oncol 2022). Even if extensively studied in combination with LEN (Morschhauser, Blood 2021), M has never been tested in combination with Bruton's tyrosine kinase (BTK) inhibitor (BTKi). Therefore, we here propose the FIL-MOZART phase 2 study assessing the combination of M+Z as salvage strategy in patients with R/R FL who have received at least one line of prior systemic therapy.

Study design and methods

FIL-MOZART (EU CT number 2023-506049-52-00) is an international, investigator initiated phase 2 trial involving 20 italian FIL centers and 5 australian centers from The Australasian Leukaemia & Lymphoma Group (ALLG). M will be provided by Roche and Z from Beigene. Beigene will also provide economic support to the study. None of the companies will be involved in study conduction data collection, data analysis, interpretation, and future scientific reporting.

Eligible adult patients must have CD20+ histologically confirmed classic FL, stage III or IV disease (or bulky stage II), at least one and up to three lines of systemic therapy containing an anti-CD20 antibody (anti-CD20 alone and/or in combination with radiotherapy is not considered as a line of therapy), adequate hematological and extra-hematological function with a need of systemic treatment by meeting GELF criteria. Patients with a history of prior exposure to a BTKi or to an anti-CD20xCD3 bispecific antibody, treatment with chimeric antigen receptor T-cell (CAR-T) therapy within 90 days prior to first therapy administration, need anticoagulation therapy, prior allogeneic hematopoietic stem cell transplantation, autoimmune disorders requiring treatment or central nervous system involvement will be excluded.

Fifty-six patients will be enrolled including at least 66% in first relapse. Eligible patients will receive a 2 week pre-phase with oral Z followed by an induction phase with M+Z. Patients responsive to induction phase with M+Z (C1-12) and achieving at least SD will receive maintenance with Z for additional 12 months (C13-24). There will be an initial safety run-in (SRI) phase of 10 patients which will be closely monitored for the observed toxicities during the first three cycles of induction (from C1D1 to C3D28). No patients will be further enrolled until SRI analyses is completed.

Primary endpoints will be CR rate (CRR) at the end of the combination therapy. Key secondary efficacy endpoints include PFS, OS, DOR, DOCR, TTNT, EFS, MRD negativity. Safety endpoints include incidence and severity of AE, including AE of special interest (CRS, ICANS and TLS).

Recruitment is planned to start from the Q3 2024.