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 EthicsCommittee (NEC) prior to the initiation of any screening or study-specificprocedures and able to understand and to comply with the requirements of the studyand the schedule of assessments.

2. Histologically documented diagnosis of cFL (CD20+ by flow cytometry orimmunohistochemistry) as defined in the International Consensus Classification ofMature Lymphoid Neoplasms (Campo E., 2022) and in the World Health OrganizationClassification (WHO) 5th edition 2022.

3. Age ≥18 years.

4. Relapsed or refractory disease. Histologic confirmation of FL relapse is notmandatory but is highly recommended.

5. At least one and up to three lines of systemic therapy containing an anti-CD20antibody (anti-CD20 alone and/or in combination with radiotherapy is not consideredas a line of therapy).

6. FL requiring systemic therapy assessed by investigator based on tumor size and/orGroupe 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 pathologyreview is not mandatory for start of treatment.

9. At least one measurable or evaluable site of disease at relapse as documented by CTscan (nodes ≥ 1.5 cm in the longest transverse diameter) or FDG-PET (avid FDGsites). Note: MRI is allowed only if CT scan cannot be performed. Patients withexclusive 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-Gaultformula, 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 ofnon-hepatic origin).

13. Subject must be able to adhere to the study visit schedule and other protocolrequirements.

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 atleast 12 months);

• surgically sterile (have had a hysterectomy or bilateral oophorectomy, tuballigation, or otherwise be incapable of pregnancy);

• if they are childbearing potential, completely abstinent (periodic abstinenceis not permitted) or if sexually active, be practicing a highly effectivemethod of birth control (e.g., prescription oral contraceptives, contraceptiveinjections, contraceptive patch, intrauterine device, double barrier method (e.g.: condoms, diaphragm, or cervical cap, with spermicidal foam, cream, orgel, male partner sterilization), before entry, and must agree to continue touse the same method of contraception throughout the study and for 30 days afterreceiving the last dose of zanubrutinib and 3 months after receiving the lastdose 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 thestudy 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 ofthe following:

• practice effective barrier contraception (e.g.: condoms) , or

• agree to practice abstinence, when this is in line with the usual lifestyle ofthe 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 (autologousstem cell transplant performed as part of consolidation to a previous line oftherapy should not be considered as a line of therapy; rituximab maintenance as partof 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 oftherapy).

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 bleedingrequiring blood transfusion or other medical intervention. History of stroke orintracranial 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 lupuserythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosisassociated with antiphospholipid syndrome, Wegener's granulomatosis, Sjögren'ssyndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, orglomerulonephritis.

14. Primary central nervous system (CNS) lymphoma or CNS involvement by lymphoma atscreening as confirmed by mandatory brain computed tomography (CT) scan and, ifclinically indicated, by lumbar puncture.

15. Subject has received any anti-cancer therapy including chemotherapy, immunotherapy,radiotherapy, investigational therapy, including targeted small molecule agentswithin 14 days prior to the first dose of study drug. If receiving glucocorticoidtreatment at screening, must be a maximum daily dose of prednisone 10 mg (orequivalent).

16. Prior treatment with chimeric antigen receptor T-cell (CAR-T) therapy within 90 daysprior to first therapy administration.

17. Any uncontrolled or significant cardiovascular disease [NYHA class ≥2].

18. Myocardial infarction within 6 months before screening

19. Unstable angina within 3 months before screening

20. New York Heart Association class III or IV congestive heart failure

21. History of clinically significant arrhythmias (eg, sustained ventriculartachycardia, ventricular fibrillation, torsades de pointes)

22. Significant history of neurologic, psychiatric, endocrinological, metabolic,immunologic, or hepatic disease that would preclude participation in the study orcompromise ability to give informed consent.

23. Any history of other active malignancies within 3 years prior to study entry, exceptfor adequately treated in situ carcinoma of the uterine cervix, basal cell carcinomaof the skin or localized squamous cell carcinoma of the skin, non-muscle-invasivebladder cancer, localized Gleason score 6 prostate cancer, previous malignancyconfined and surgically resected with curative intent.

24. Evidence of other clinically significant uncontrolled condition(s) including, butnot limited to:

25. Uncontrolled and/or active systemic infection (viral, bacterial or fungal),including active ongoing infection from SARS-CoV-2;

26. Chronic or acute hepatitis B virus (HBV) or hepatitis C (HCV) requiringtreatment. Note: subjects with serologic evidence of prior vaccination to HBV (i.e. hepatitis B surface (HBs) antigen (Ag) negative, anti-HBs antibodypositive and anti-hepatitis B core (HBc) antibody negative) or positiveanti-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 PCRnegative for HCV-RNA;

27. HIV seropositivity.

28. Pregnant or lactating women. If female, the patient is pregnant or breast-feeding.

29. Severe or debilitating pulmonary disease.

30. Unable to swallow capsules or disease significantly affecting gastrointestinalfunction such as malabsorption syndrome, resection of the stomach or small bowel,bariatric surgery procedures, symptomatic inflammatory bowel disease, or partial orcomplete bowel obstruction.

31. Underlying medical conditions that, in the investigator's opinion, will render theadministration of study drug hazardous or obscure the interpretation of toxicity orAEs.

32. Major surgery within 4 weeks of the first dose of study drug.

33. Vaccination or requirement for vaccination with a live vaccine within 28 days priorto the first dose of study drug or at any time during planned study treatment.

34. Ongoing alcohol or drug addiction or any psychiatric condition(s) which wouldcompromise ability to comply with study procedures.

35. Hypersensitivity to zanubrutinib or mosunetuzumab or any of the other ingredients ofthe applicable study drugs.

36. Active and/or ongoing autoimmune anemia and/or autoimmune thrombocytopenia (eg,idiopathic thrombocytopenia purpura).