Phase II Study of Glofitamab With Venetoclax +/- Zanubrutinib in High-risk Mantle-cell Lymphoma

In cohort A, participant must meet the following inclusion criteria: 1. Participant must be primary refractory or in progression within 24 months from initiation of first line treatment (POD24 defined as time between D1C1 of the first treatment line and ICF signature)) (including an anti-CD20 combined with chemotherapy). Participant previously exposed to BTK inhibitor at first line is eligible. Participant in failure of CAR-T cell first line is eligible. 2. Primary refractory participants (i.e., with a progressive disease) to the BTKi and Venetoclax combination will not be eligible. In cohort B, participant must meet the following inclusion criterion: 3. Participant must be R/R MCL and refractory or progressive to a BTK inhibitor given in a previous line of treatment (the number of treatment lines is not limited). If first progression, time from diagnosis (defined as D1C1 of the first treatment line) to inclusion (defined as the date of ICF signature) must be superior to 24 months. 4. Participant previously exposed to Bcl-2 therapy and/or relapsing post CAR-T cell therapy is eligible, except if they presented a progressive disease under BTKi and Venetoclax combination. In cohort C, participant must meet the following inclusion criteria: 5. Participant not previously treated for mantle cell lymphoma. 6. Participant at high risk of relapse presenting at least two of the following risk factors: 1. TP53 mutation, del17p, or p53 expression (IHC) \> 50%, 2. blastoïd variant, 3. complex karyotype defined as 3 or more abnormalities additional to t(11;14), 4. c-myc rearrangement (FISH), 5. Ki67≥30%, 6. high MIPI score, (or MIPI simplified) 7. high MIPI-combined score ((ie high MIPI score + Ki67≥30%): this criterion alone is sufficient. Participant must meet all of the following additional criteria to be enrolled in the study for cohort A, B and C: 7. Participant is ≥ 18 years and \< 80 years of age at the time of signing the informed consent form (ICF). 8. Participant understood and voluntarily signed and dated an informed consent prior to any study-specific assessments/procedures being conducted. 9. Participant with histologically proven mantle cell lymphoma (latest WHO classification). The diagnosis has to be confirmed by phenotypic expression of CD5, CD20 and cyclin D1 or the t(11;14) translocation. Diagnostic tissue should be available for central pathology review and ancillary molecular studies. 10. Bi-dimensionally measurable disease defined by at least one single node or tumor lesion ≥ 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. 11. Stage II-IV disease, 12. ECOG performance status of 0, 1, 2. 13. Life expectancy of more than 3 months. 14. Adequate renal function as demonstrated by a creatinine clearance \> 30 mL/min; calculated by the Cockcroft Gault formula or MDRD formula. 15. Adequate hepatic function per local laboratory reference range as follow (unless if due to lymphoma involvement): 1. Aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 2.5x upper limit of normal (ULN) 2. Bilirubin \< 1.5 x ULN (unless bilirubin rise is due to Gilbert's syndrome or of non-hepatic origin. in which case total bilirubin should be \< 3 x ULN). 16. Women of childbearing potential (WOCBP) (refer to section 14.7 for more details) must have negative results for highly effective urine/serum pregnancy test 10-14 days prior to Day 1 of Cycle 1 and within 24 hours prior to day 1 Cycle 1 prior to initiating study treatment and agree to abstain from becoming pregnant or breastfeeding during study participation and until at least 18 months after C1 with Obinutuzumab, or 3 months after the final dose of tocilizumab (if applicable), or 2 months after the final dose of Glofitamab, or or 1 month after the final dose of Zanubrutinib (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 the treatment period and for at least 18 months after the final dose of Obinutuzumab, 3 months after the final dose of tocilizumab (if applicable), 2 months after the final dose 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). 17. Men of reproductive potential (refer to section 14.6 for more details) agree to remain abstinent (from heterosexual intercourse) or use effective methods of birth control with a non-pregnant female partner of childbearing potential or a pregnant female partner and to refrain from donating sperm, during the treatment period and for at least 3 months after the final dose of Obinutuzumab, 2 months after the final dose of Glofitamab, 2 months after the final dose tocilizumab (if applicable), 30 days after the final dose of Venetoclax, 1 week after the final dose of Zanubrutinib (if applicable). 18. Adequate bone marrow function as defined by: 1. Absolute neutrophil count (ANC) ≥ 1000/mm3, except for participants with bone marrow involvement in which ANC must be ≥ 500/mm3. 2. Platelet ≥ 75,000/mm3, except for participants with bone marrow involvement in which the platelet count must be ≥ 50,000/mm3. 19. Participant covered by any social security system (France). 20. Participant who understands and speaks one of the country official languages unless local regulation authorizes independent translators. 21. Participant with a SARS-COV2 vaccination status in line with local National guidelines/recommendations (COSV, ANRS MIE). 22. Participant must be willing and able to comply with protocol-mandated hospitalization upon administration of the first two doses of Glofitamab. Participant must also be willing to comply with all study-related procedures. 23. Adverse events from prior anti-cancer t