Study With Mosunetuzumab and Zanubrutinib in R/R Follicular Lymphoma Patients

Inclusion Criteria: 1. Able to provide written informed consent form approved by the National Ethics Committee (NEC) prior to the initiation of any screening or study-specific procedures and able to understand and to comply with the requirements of the study and the schedule of assessments. 2. Histologically documented diagnosis of cFL (CD20+ by flow cytometry or immunohistochemistry) as defined in the International Consensus Classification of Mature Lymphoid Neoplasms (Campo E., 2022) and in the World Health Organization Classification (WHO) 5th edition 2022. 3. Age ≥18 years. 4. Relapsed or refractory disease. Histologic confirmation of FL relapse is not mandatory but is highly recommended. 5. 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). 6. FL requiring systemic therapy assessed by investigator based on tumor size and/or Groupe d'Etude des Lymphomes Folliculaires criteria. 7. Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤ 2. 8. Availability of histological material for centralized revision. Central pathology review is not mandatory for start of treatment. 9. At least one measurable or evaluable site of disease at relapse as documented by CT scan (nodes ≥ 1.5 cm in the longest transverse diameter) or FDG-PET (avid FDG sites). Note: MRI is allowed only if CT scan cannot be performed. Patients with exclusive bone marrow involvement are eligible. 10. Adequate hematological counts defined as follows: * Absolute neutrophil count (ANC) \> 1.0 x 109/L; * Platelet count ≥ 75 x 109/L; * Hemoglobin ≥ 9 g/dL. 11. Adequate renal function defined as creatinine clearance ≥ 40 mL/min (Cockcroft-Gault formula, normalized to 1.72 m2). 12. Adequate hepatic function per local laboratory reference range as follows: * Aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 2.5 x ULN; * Bilirubin ≤1.5 x ULN (unless bilirubin rise is due to Gilbert's syndrome or of non-hepatic origin). 13. Subject must be able to adhere to the study visit schedule and other protocol requirements. 14. Subject must be able to swallow capsules or tablets. 15. Women must be: * postmenopausal for at least 1 year (must not have had a natural menses for at least 12 months); * surgically sterile (have had a hysterectomy or bilateral oophorectomy, tubal ligation, or otherwise be incapable of pregnancy); * if they are childbearing potential, completely abstinent (periodic abstinence is not permitted) or if sexually active, be practicing a highly effective method of birth control (e.g., prescription oral contraceptives, contraceptive injections, contraceptive patch, intrauterine device, double barrier method (e.g.: condoms, diaphragm, or cervical cap, with spermicidal foam, cream, or gel, male partner sterilization), before entry, and must agree to continue to use the same method of contraception throughout the study and for 30 days after receiving the last dose of zanubrutinib and 3 months after receiving the last dose of mosunetuzumab. 16. Women of childbearing potential must have a negative pregnancy test at screening. 17. Men must agree to use an acceptable method of contraception for the duration of the study and for 1 week after receiving the last dose of study drug. 18. Male even if surgically sterilized (i.e., status post vasectomy) must agree to 1 of the following: * practice effective barrier contraception (e.g.: condoms) , or * agree to practice abstinence, when this is in line with the usual lifestyle of the subject (periodic abstinence is not permitted). Exclusion Criteria: 1. Histological diagnosis different from cFL (Campo E., 2022). 2. R/R FL who were treated with more than three lines of previous treatment (autologous stem cell transplant performed as part of consolidation to a previous line of therapy should not be considered as a line of therapy; rituximab maintenance as part of a previous line of therapy should not be considered as a line of therapy; radiotherapy alone or in combination with rituximab is not considered a line of therapy). 3. Patients with stage I or II (limited stage) suitable for RT alone treatment. 4. Prior exposure to a Bruton's tyrosine kinase (BTK) inhibitor (BTKi). 5. Prior exposure to an anti-CD20xCD3 bispecific antibody (bsAbs). 6. Need of anticoagulation with warfarin or equivalent vitamin K antagonists (e.g. phenprocoumon). Requires ongoing treatment with a strong CYP3A inducer. 7. Evidence or any history of transformation from FL to other aggressive histology. 8. Prior allogeneic hematopoietic stem cell transplantation. 9. History of severe bleeding disorder (G\>3), or history of spontaneous bleeding requiring blood transfusion or other medical intervention. History of stroke or intracranial hemorrhage within 6 months before first dose of study drug 10. Life expectancy \< 6 months. 11. History of progressive multifocal leukoencephalopathy (PML). 12. History of hemophagocytic lymphohistiocytosis (HLH) or chronic active EBV. 13. History of autoimmune disease, including, but not limited to: myocarditis, pneumonitis, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener's granulomatosis, Sjögren's syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, or glomerulonephritis. 14. Primary central nervous system (CNS) lymphoma or CNS involvement by lymphoma at screening as confirmed by mandatory brain computed tomography (CT) scan and, if clinically indicated, by lumbar puncture. 15. Subject has received any anti-cancer therapy including chemotherapy, immunotherapy, radiotherapy, investigational therapy, including targeted small molecule agents within 14 days prior to the first dose of study drug. If receiving glucocorticoid treatment at screening, must be a maximum daily dose of prednisone 10 mg (or equivalent). 16. Prior treatment with chimeric antigen receptor T-cell (CAR-T) therapy within 90 days prior to first therapy administration. 17. Any uncontrolled or significant cardiovascular disease \[NYHA class ≥2\]. 1. Myocardial infarction within 6 months before screening 2. Unstable angina within 3 months before screening 3. New York Heart Association class III or IV congestive heart failure 4. History of clinically significant arrhythmias (eg, sustained ventricular tachycardia, ventricular fibrillation, torsades de pointes) 18. Significant history of neurologic, psychiatric, endocrinological, metabolic, immunologic, or hepatic disease that would preclude participation in the study or compromise ability to give informed consent. 19. Any history of other active malignancies within 3 years prior to study entry, except for adequately treated in situ carcinoma of the uterine cervix, basal cell carcinoma of the skin or localized squamous cell carcinoma of the skin, non-muscle-invasive bladder cancer, localized Gleason score 6 prostate cancer, previous malignancy confined and surgically resected with curative intent. 20. Evidence of other clinically significant uncontrolled condition(s) including, but not limited to: 1. Uncontrolled and/or active systemic infection (viral, bacterial or fungal), including active ongoing infection from SARS-CoV-2; 2. Chronic or acute hepatitis B virus (HBV) or hepatitis C (HCV) requiring treatment. Note: subjects with serologic evidence of prior vaccination to HBV (i.e. hepatitis B surface (HBs) antigen (Ag) negative, anti-HBs antibody positive and anti-hepatitis B core (HBc) antibody negative) or positive anti-HBc antibody from previous infection or intravenous immunoglobulins (IVIG) may participate; inactive carriers (HBsAg positive with undetectable HBV- DNA) are eligible. Patients with presence of HCV antibody are eligible only if PCR negative for HCV-RNA; 21. HIV seropositivity. 22. Pregnant or lactating women. If female, the patient is pregnant or breast-feeding. 23. Severe or debilitating pulmonary disease. 24. Unable to swallow capsules or disease significantly affecting gastrointestinal function such as malabsorption syndrome, resection of the stomach or small bowel, bariatric surgery procedures, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction. 25. Underlying medical conditions that, in the investigator's opinion, will render the administration of study drug hazardous or obscure the interpretation of toxicity or AEs. 26. Major surgery within 4 weeks of the first dose of study drug. 27. Vaccination or requirement for vaccination with a live vaccine within 28 days prior to the first dose of study drug or at any time during planned study treatment. 28. Ongoing alcohol or drug addiction or any psychiatric condition(s) which would compromise ability to comply with study procedures. 29. Hypersensitivity to zanubrutinib or mosunetuzumab or any of the other ingredients of the applicable study drugs. 30. Active and/or ongoing autoimmune anemia and/or autoimmune thrombocytopenia (eg, idiopathic thrombocytopenia purpura).