A Phase II Study Evaluating Glofitamab in Combination With Venetoclax Plus Zanubrutinib or Venetoclax Alone in Subjects With Untreated or Relapsed/Refractory High-risk Mantle-cell Lymphoma

Inclusion Criteria:

In cohort A, subject must meet the following inclusion criteria:

1. Subject must be primary refractory or in progression within 24 months frominitiation of first line treatment (POD24 defined as time between D1C1 of the firsttreatment line and ICF signature)) (including an anti-CD20 combined withchemotherapy). Subject previously exposed to BTK inhibitor at first line iseligible. Subject in failure of CAR-T cell first line is eligible.

2. Primary refractory subjects (ie with a progressive disease) to the BTKi andVenetoclax combination will not be eligible. In cohort B, subject must meet the following inclusion criterion:

3. Subject must be R/R MCL and refractory or progressive to a BTK inhibitor given in aprevious line of treatment (the number of treatment lines is not limited). If firstprogression, time from diagnosis (defined as D1C1 of the first treatment line) toinclusion (defined as the date of ICF signature) must be superior to 24 months.

4. Subject previously exposed to Bcl-2 therapy and/or relapsing post CAR-T cell therapyis eligible, except if they presented a progressive disease under BTKi andVenetoclax combination. In cohort C, subject must meet the following inclusion criteria:

5. Subject not previously treated for mantle cell lymphoma.

6. Subject at high risk of relapse presenting at least two of the following riskfactors:

7. TP53 mutation, del17p, or p53 expression (IHC) > 50%,

8. blastoïd variant,

9. complex karyotype,

10. c-myc rearrangement (FISH),

11. Ki67≥30%,

12. high MIPI score, (or MIPI simplified)

13. high MIPI-combined score ((ie high MIPI score + Ki67≥30%): this criterion aloneis sufficient. Subject must meet all of the following additional criteria to be enrolled in thestudy for cohort A, B and C:

14. Subject is ≥ 18 years and < 80 years of age at the time of signing the informedconsent form (ICF).

15. Subject understood and voluntarily signed and dated an informed consent prior to anystudy-specific assessments/procedures being conducted.

16. Subject with histologically proven mantle cell lymphoma (latest WHO classification).The diagnosis has to be confirmed by phenotypic expression of CD5, CD20 and cyclinD1 or the t(11;14) translocation. Diagnostic tissue should be available for centralpathology review and ancillary molecular studies.

17. Bi-dimensionally measurable disease defined by at least one single node or tumorlesion ≥ 1.5 cm assessed by CT scan, or one bi-dimensionally measurable (≥1 cm)extranodal lesion, as measured on CT scan, and/or clinical examination.

18. Stage II-IV disease,

19. ECOG performance status of 0, 1, 2.

20. Life expectancy of more than 3 months.

21. Adequate renal function as demonstrated by a creatinine clearance > 30 mL/min;calculated by the Cockcroft Gault formula or MDRD formula.

22. Adequate hepatic function per local laboratory reference range as follow (unless ifdue to lymphoma involvement):

23. Aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 2.5x upper limitof normal (ULN)

24. Bilirubin < 1.5 x ULN (unless bilirubin rise is due to Gilbert's syndrome or ofnon-hepatic origin. in which case total bilirubin should be < 3 x ULN).

25. Women of childbearing potential (WOCBP) (refer to section 14.7 for more details)must have negative results for highly effective urine/serum pregnancy test 10-14days prior to Day 1 of Cycle 1 and within 24 hours prior to day 1 Cycle 1 prior toinitiating study treatment and agree to abstain from becoming pregnant orbreastfeeding during study participation and until at least 18 months after C1 withObinutuzumab, or 3 months after the final dose of tocilizumab (if applicable), or 2months after the final dose of Glofitamab, or or 1 month after the final dose ofZanubrutinib (if applicable), or 30 days after the final dose of Venetoclax,whichever is longer. WOCBP agree to remain abstinent (from heterosexual intercourse)or use two methods of contraception, and to refrain from donating eggs, during thetreatment period and for at least 18 months after the final dose of Obinutuzumab, 3months after the final dose of tocilizumab (if applicable), 2 months after the finaldose of Glofitamab, 1 month after the final dose of Zanubrutinib (if applicable),and 30 days after the final dose of Venetoclax (refer to section 14.6).

26. Men of reproductive potential (refer to section 14.6 for more details) agree toremain abstinent (from heterosexual intercourse) or use effective methods of birthcontrol with a non-pregnant female partner of childbearing potential or a pregnantfemale partner and to refrain from donating sperm, during the treatment period andfor at least 3 months after the final dose of Obinutuzumab, 2 months after the finaldose of Glofitamab, 2 months after the final dose tocilizumab (if applicable), 30days after the final dose of Venetoclax, 1 week after the final dose of Zanubrutinib (if applicable).

27. Adequate bone marrow function as defined by:

28. Absolute neutrophil count (ANC) ≥ 1000/mm3, except for subjects with bonemarrow involvement in which ANC must be ≥ 500/mm3.

29. Platelet ≥ 75,000/mm3, except for subjects with bone marrow involvement inwhich the platelet count must be ≥ 50,000/mm3 .

30. Subject covered by any social security system (France).

31. Subject who understands and speaks one of the country official languages unlesslocal regulation authorizes independent translators.

32. Subject with a SARS-COV2 vaccination status in line with local Nationalguidelines/recommendations (COSV, ANRS MIE).

33. Subject must be willing and able to comply with protocol-mandated hospitalizationupon administration of the first two doses of Glofitamab. Subject must also bewilling to comply with all study-related procedures.

34. Adverse events from prior anti-cancer therapy must have resolved to Grade ≤ 1 (hematological toxicities excepted)

• Exclusion Criteria:

Subject who meets any of the following criteria will be excluded from enrollment in the study study for cohort A, B and C:

1. Proven or previously known CD20 negative status on FFPE IHC at time of MCL relapseor diagnosis.

2. For subjects in Cohort A and B: previously refractory to treatment by BTK inhibitorand Bcl-2 therapy combination.

3. Any prior therapy with a bispecific antibody targeting CD3 and CD20.

4. Current or past history of central nervous system or meningeal involvement bylymphoma.

5. Use of any standard or experimental anti-cancer drug therapy including biologicalagents (e.g. monoclonal antibodies within 30 days of the start (Day 1) of studytreatment, except for BTKi for subjects included in cohort B, that can be pursueduntil C1D1 and except for topical treatment or hormone treatment if criterion 33 isrespected. Corticosteroid treatment <25 mg/day prednisone or equivalent is allowedwithin 2 weeks prior to Obinutuzumab infusion.

6. LVEF < 50% as determined by echocardiography or isotopic method.

7. Clinically significant cardiovascular disease such as uncontrolled, unstable orsymptomatic arrhythmias, unstable angina, congestive heart failure, or myocardialinfarction within 6 months of screening, or any Class III (moderate) or ClassIV(severe) cardiac disease as defined by the New York Heart Association FunctionalClassification or Objective Assessment Class C or D cardiac disease. Heartrate-corrected QT interval > 480 milliseconds based on Fridericia's formula.;History of Mobitz II second-degree or third-degree heart block without a permanentpacemaker in place; Uncontrolled hypertension as indicated by a minimum of 2consecutive blood pressure measurements, at screening, showing systolic bloodpressure > 170 mmHg and diastolic blood pressure > 105 mmHg and/or uncontrolledhypertension with systolic blood pressure>140mmHg despite a well conducthypertensive treatment for at least 6 months

8. Hemoglobin level < 8g/dL; Absolute Neutrophil count <1 G/L (<0,5G/L if related tolymphoma); Platelets < 75 G/L (< 50 G/L if related to lymphoma),

9. Major surgery within 28 days before screening.

10. Require the use of anticoagulation by warfarin or equivalent vitamin K antagonists (e.g., phenprocoumone)

11. Requires treatment with a moderate or a strong CYP3A inhibitor or inducer..

12. Vaccinated with live, attenuated vaccines within 4 weeks of enrollment (except COVIDvaccine) or anticipation that such a live attenuated vaccine will be required duringthe study.

13. Known hypersensitivity to active substances or to any of the excipients. OrContraindication to any study treatments.

14. Known allergy to all xanthine oxidase inhibitors or rasburicase.

15. Previously documented G6DP deficiency.

16. Severe prior reactions to anti CD20 monoclonal antibodies or prior significanttoxicity (other than thrombocytopenia) with Bcl-2 inhibitor.

17. Prior treatment with systemic immunosuppressive medications (including, but notlimited to, cyclophosphamide, azathioprine, methotrexate, thalidomide, andanti-tumor necrosis factor agents), within 2 weeks or five half-lives (whichever isshorter) prior to first dose of study treatment.

18. 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.

19. History of severe bleeding disorder such as hemophilia A, hemophilia B, vonWillebrand disease, or history of spontaneous bleeding requiring blood transfusionor other medical intervention.

20. Current or history of CNS disease, such as stroke, epilepsy, CNS vasculitis,neurodegenerative disease: or intracranial hemorrhage: Subjects with a history ofstroke or intracranial hemorrhage who have not experienced a stroke or transientischemic attack or intracranial hemorrhage within the past 2 years and have noresidual neurologic deficits, as judged by the investigator, are allowed.

21. Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection (excluding fungal infections of nail beds) at study enrollment or any major episodeof infection (as evaluated by the investigator) within 4 weeks prior to the firststudy treatment.

22. Known Human Immunodeficiency Virus (HIV), for subjects with unknown HIV status, HIVtesting will be performed at screening if required by local regulations.

23. Positive test results for hepatitis C virus (HCV) antibody: Subjects who arepositive for HCV antibody are eligible only if PCR is negative for HCV RNA.

24. Positive test results for hepatitis B virus (HBV) infection (defined as positiveHbsAg serology) Subjects with occult or prior HBV infection (defined as negativeHbsAg and positive HbcAb) may be included if HBV DNA is undetectable, provided thatthey are willing to undergo DNA testing on Day 1 of every cycle and every threemonths for at least 12 months after the last cycle of study treatment andappropriate antiviral therapy.

25. Positive SARS-CoV-2 test within 7 days prior to enrollment. Rapid antigen testresult is also acceptable.

26. Documented SARS-CoV-2 infection within 6 months of first study treatment (Cycle 1Day 1): Subjects may be eligible if they have no persistent respiratory symptoms, noevidence of lung infiltrates on chest CT, and have a negative PCR during the first 30 days prior to first study treatment (Cycle 1 Day 1)

27. Suspected or latent tuberculosis (confirmed by positive interferon-γ release assay)

28. Known or suspected chronic active Epstein-Barr viral infection or evidence ofpositive HTLV1 serology.

29. Any life-threatening illness, medical condition, or organ system dysfunction which,in the investigator opinion, could compromise the subject's safety, interfere withthe absorption or metabolism of study treatments, or put the study outcomes at unduerisk.

30. Prior allogenic SCT is allowed if no active GVHD and no active immune-suppressivetreatment (to be discussed with the medical monitor).

31. Active autoimmune disease requiring treatment:

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

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

34. Subjects with a history of autoimmune hepatitis, systemic lupus erythematosus,inflammatory bowel disease, vascular thrombosis associated withantiphospholipid syndrome, Wegener granulomatosis, Sjögren syndrome, multiplesclerosis, or glomerulonephritis will be excluded.

35. Subjects with a history of immune thrombocytopenic purpura, autoimmunehemolytic anaemia, Guillain-Barré syndrome, myasthenia gravis, myositisrheumatoid arthritis, vasculitis, or other autoimmune diseases will be excludedunless they have not required systemic therapy in the last 12 months.

36. Subject with history of confirmed progressive multifocal leukoencephalopathy (PML)

37. Active malignancy other than the one treated in this research. Prior history ofmalignancies unless the subject has been free of the disease for ≥ 2 years. However,subjects with the following history/concurrent conditions are allowed:

38. Basal or squamous cell carcinoma of the skin

39. Carcinoma in situ of the cervix

40. Carcinoma in situ of the breast

41. Incidental histologic finding of prostate cancer (T1a or T1b) using the tumor,nodes, metastasis [TNM] clinical staging system.

42. Pregnant, planning to become pregnant or lactating WOCBP.

43. Any significant medical conditions, laboratory abnormality or psychiatric illnesslikely to interfere with participation or understanding of study requirements (according to the investigator's decision).

44. Severe or debilitating pulmonary disease, history of interstitial lung disease,noninfectious pneumonitis, or uncontrolled lung diseases, including but not limitedto pulmonary fibrosis and acute lung diseases.

45. Known or suspected history of HLH unless related to lymphoma.

46. Clinically significant history of cirrhotic liver disease, ongoing, drug-inducedliver injury, alcoholic liver disease, nonalcoholic steatohepatitis, primary biliarycirrhosis, ongoing extrahepatic obstruction caused by cholelithiasis, cirrhosis ofthe liver, or portal hypertension.

47. INR or PT > 1.5 x ULN, or Quick percentage < 70% (if Quick percentage used in lieuof time-based units for reporting PT), in the absence of therapeuticanticoagulation.

48. aPTT >1.5 x ULN in the absence of therapeutic anticoagulation or a lupusanticoagulant.

49. Prior solid organ transplantation.

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

51. Person hospitalized without consent.

52. Adult person under legal protection.

NB: for 42, 43, 44 if there is an individual benefit for such subjects, an Ethics Committee will have to be informed case by case.