Mosunetuzumab-Lenalidomide Versus Investigator Choices in Patients With Relapsed or Refractory Marginal Zone Lymphoma

Inclusion Criteria:

1. Have a diagnosis of MZL, of extranodal (EMZL) or splenic (SMZL based on the Matutesscore and CD20 + CD11c + CD180 + CD43 + CD200 expression and validated by acentralized review) or nodals (NMZL) subtypes. In case of large dissemination,disseminated MZL will be included as DMZL and included in NMZL subtype.

2. Have been treated with at least one prior systemic treatment and not more than threeprior lines. Previous line must include at least one systemic line with a drugtargeting CD20 (monoclonal antibody at least 2 cycles) with or without chemotherapy (R-CHOP, R-Bendamustine, R-CVP, R-Chlorambucil at least 2 cycles) or targetedtreatment such as Ibrutinib (at least 1 month). Patients should not have receivedLenalidomide before. Prior local therapy (including surgery, radiotherapyantibiotics for H. pylori-positive gastric lymphoma, and antiviral for hepatitis Cvirus) is not considered as one line of treatment

3. Signed Informed Consent Form

4. Age ≥ 18 years at the time of signing the informed consent form

5. Ability to comply with the study protocol and procedures and requiredhospitalizations, in the investigator's judgement

6. Eastern Cooperative Oncology Group (ECOG) performance score (PS) of ≤ 2

7. Have a symptomatic disease requiring a systemic treatment

8. Not eligible for a local treatment including radiotherapy or surgery

9. Stage I disease of EMZL, SMZL or NMZL may be eligible only if not candidate to localtherapy (surgery or radiotherapy).

10. Measurable disease in at least two perpendicular dimensions on an imaging scan isdefined as: lymph node or nodal mass bi-dimensional measurement with ≥ 15 mm inlongest transverse diameter or the short diameter must measure ≥ 10 mm regardless ofthe longest transverse diameter. Spleen is considered as a measurable disease if vertical axis is higher than 13 cm.

11. Adequate hematopoietic function at screening as follows unless cytopenia is clearlydue to marrow involvement of MZL or hypersplenism or autoimmune thrombocytopenia:

11.1. Platelet count ≥ 75 G/L; in cases of thrombocytopenia clearly due to marrowinvolvement of MZL or hypersplenism or auto-immune thrombocytopenia, platelet countshould be ≥ 30 G/L Washout platelet transfusion is 7 days between transfusion and D1of starting treatment 11.2. Absolute Neutrophil Count (ANC ) ≥ 1 G/L unlessneutropenia is clearly due to marrow involvement of MZL or hypersplenism.Granulocyte Colony-Stimulating Factor (G-CSF) is not allowed within 7 days beforestarting treatment 11.3. Total hemoglobin ≥ 8 g/dL unless anemia is clearly due tomarrow involvement of MZL or hypersplenism or autoimmune hemolytic anemia. Washouterythrocyte transfusion is 7 days between transfusion and D1 of starting treatment

12. Serum total bilirubin ≤ 1.5 x the upper limit of normal (ULN) (or ≤3 x ULN forpatients with Gilbert syndrome),

13. Aspartate Transaminase (AST) or ALanine Transaminase (ALT) ≤ 2.5 x ULN, unlessdirectly attributable to the patient's MZL

14. Measured or estimated creatinine clearance ≥ 40 mL/min by institutional standardmethod

15. Patients who are hepatitis B surface antigen (HBsAg) negative and hepatitis B coreantibody (HBcAb) positive, must be negative for hepatitis B virus (HBV) polymerasechain reaction (PCR) to be eligible for study participation. Patients who arehepatitis B surface antigen (HBsAg) negative, hepatitis B surface antibody (anti-HBsAb) positive and hepatitis B core antibody (HBcAb) negative are eligible,

17. Contraception: 16.1. For women of childbearing potential (WOCBP) (refer tosection 14.6.1 and 14.6.1.1): Serum test pregnancy at screening and Day 1before first dose. And then monthly until end of treatment. Efficientcontraceptive method is required during the treatment period (including periodsof treatment interruption), for at least 28 days after the final dose ofLenalidomide (if applicable), 3 months after the final dose of Mosunetuzumab (if applicable), 6 months after the final dose of chemotherapies (ifapplicable) and 12 months after the final dose of Rituximab (if applicable).

16.2. For men: agreement to remain abstinent (refrain from heterosexual intercourse)or use a condom, and agreement to refrain from donating sperm, as defined below:With a female partner of childbearing potential or pregnant female partner, men mustremain abstinent or use a condom during the treatment period (including periods oftreatment interruption), and for at least 28 days after the final dose ofLenalidomide (if applicable), 3 months after the final dose of Mosunetuzumab andTocilizumab (if applicable), 6 months after the final dose of chemotherapies (ifapplicable) and 12 months after the final dose of Rituximab) (if applicable).

17. Patient covered by any social security system (France)

Exclusion Criteria:

1. MZL with histologic transformation to high-grade lymphoma

2. Pregnant or breastfeeding or intending to become pregnant during the study or within 28 days after the final dose of Lenalidomide, 3 months after the final dose ofMosunetuzumab and Tocilizumab (if applicable), 6 months after the final dose ofchemotherapies and 12 months after the final dose of Rituximab (if applicable).Women of childbearing potential must have a negative serum pregnancy test resultwithin 7 days prior to initiation of study treatment.

3. Participants who have received any of the following treatments prior to study entry:

• Treatment with Mosunetuzumab or other CD20/CD3-directed bispecific antibodies

• Allogeneic stem cell transplant

4. Participants who have received any of the following treatments, whetherinvestigational or approved, within the respective time periods prior to initiationof study treatment:

• Radiotherapy within 2 weeks prior to the first dose of study treatment

• Autologous stem cell transplant within 100 days prior to first study treatment

• Use of monoclonal antibodies within 4 weeks prior to first study treatment

• Systemic immunosuppressive medications (including, but not limited to,Cyclophosphamide, Azathioprine, Methotrexate, Thalidomide, and anti-tumornecrosis factor agents) within 2 weeks prior to first dose of study treatment (C1D1); Systemic corticosteroid treatment <20 mg/day prednisone or equivalentand inhaled corticosteroids are permitted. Last dose of corticosteroid ≥20mg/day prednisone or equivalent will not be permitted during the last 15 daysbefore inclusion. Administration of acute, low-dose, systemic immunosuppressant medications (e.g.,single dose of 4 mg/day of dexamethasone for nausea or B-symptoms) is permittedduring 4 days without washout.

• Any other anti-cancer investigational therapy within 4 weeks prior toinitiation of study treatment.

5. Received a live, attenuated vaccine within 4 weeks before first dose of studytreatment, or in whom it is anticipated that such a live attenuated vaccine will berequired during the study period or within 5 months after the final dose of studytreatment, except for acute pandemic situation such COVID19

6. Active or history of Central Nervous System (CNS) lymphoma or leptomeningealinfiltration

7. History of severe allergic or anaphylactic reactions to humanized or murinemonoclonal antibody therapy (or recombinant antibody-related fusion proteins) -grade 3 and 4

8. Known hypersensitivity to biopharmaceuticals produced in CHO cells or any componentof the Mosunetuzumab, Rituximab, Tocilizumab, Lenalidomide, or Thalidomideformulation, including Mannitol

9. Patients unable to receive adequate prophylaxis and/or therapy for thromboembolicevents (aspirin or low molecular weight heparin)

10. History of prior malignancy, except for conditions as listed below if patients haverecovered from the acute side effects incurred as a result of previous therapy:

• Malignancies treated with curative intent and with no known active diseasepresent for ≥2 years before enrollment

• Adequately treated non-melanoma skin cancer or lentigo maligna without evidenceof disease

• Adequately treated cervical carcinoma in situ without evidence of disease

• Surgically/adequately treated low grade, early stage I, localized prostate insitu carcinoma

11. Participants with infections requiring IV treatment with antibiotics orhospitalization (Grade 3 or 4) within the last 4 weeks prior to inclusion or knownactive bacterial, viral (including SARS-CoV-2), fungal, mycobacterial, parasitic, orother infection (excluding fungal infections of nail beds),

12. Evidence of any significant, concomitant disease that could affect compliance withthe protocol or interpretation of results, including, but not limited to:

• Significant cardiovascular disease [e.g., Objective Class C or D heart diseases (cf. Classes of Heart Failure | American Heart Association)], myocardialinfarction within the previous 6 months, unstable arrhythmia, or unstableangina)

• Significant pulmonary disease (such as obstructive pulmonary disease or historyof bronchospasm)

• Clinically significant history of liver disease, including viral or otherhepatitis, or cirrhosis

• Current or past history of CNS disease, such as stroke, epilepsy, CNSvasculitis, or neurodegenerative disease. Participants with a history of strokewho have not experienced a stroke or transient ischemic attack in the past 1year and have no residual neurologic deficits as judged by the investigator areallowed. Participants with a history of epilepsy who have had no seizures inthe past 2 years with or without anti-epileptic medications can be eligible.

13. History of confirmed progressive multifocal leukoencephalopathy (PML)

14. Known Positive serologic HIV test at screening

15. Acute or chronic hepatitis C virus (HCV) infection Participants who are positive forHCV antibody must be negative for HCV by polymerase chain reaction (PCR) to beeligible for study participation.

16. Known or suspected history of hemophagocytic lymphohistiocytosis

17. Known or suspected chronic active Epstein-Barr virus (EBV) infection within the last 4 weeks prior to inclusion

18. History of erythema multiforme, Grade ≥3 rash, or blistering following priortreatment with immunomodulatory derivatives

19. History of interstitial lung disease (ILD), drug-induced pneumonitis, and autoimmunepneumonitis

20. Active autoimmune disease requiring treatment

21. History of autoimmune disease, including, but not limited to, myasthenia gravis,myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis,inflammatory bowel disease, vascular thrombosis associated with antiphospholipidsyndrome, Wegener granulomatosis, Sjögren syndrome, Guillain-Barré syndrome,multiple sclerosis, vasculitis, or glomerulonephritis; except:

• Patients with a history of autoimmune-related hypothyroidism on a stable doseof thyroid replacement hormone may be eligible.

• Patients with controlled Type 1 diabetes mellitus who are on an insulin regimenare eligible for the study.

• Patients with a history of disease-related immune thrombocytopenic purpura orautoimmune hemolytic anemia may be eligible.

• Patients with a remote history of, or well-controlled autoimmune disease, witha treatment-free interval from immunosuppressive therapy for 12 months may beeligible after review and discussion with the Medical Monitor.

22. Recent major surgery with risk of bleeding within 4 weeks prior to first studytreatment administration (C1D1)

23. History of solid organ transplantation

24. Any serious medical condition or abnormality in clinical laboratory tests that, inthe investigator's judgment, precludes an individual's safe participation in andcompletion of the study

25. Person deprived of his/her liberty by a judicial or administrative decision

26. Person hospitalized without consent

27. Adult person under legal protection

28. Adult person unable to provide informed consent because of intellectual impairment,any serious medical condition, laboratory abnormality or psychiatric illness

29. Patient unable to receive at least one of the three regimens of the comparator arm (ICT). As in usual practice, physician has to verify the absence of contraindicationto the use of the drugs, hypersensitivity, and to take into account the lymphomahistory and previous treatment scheme used.