A Phase II Trial Evaluating Glofitamab, a Bispecific CD3xCD20 Antibody for Relapse/Refractory Lymphomas After CAR T-cells Therapy

• Patients who received CAR T-cells therapy for R/R DLBCL (cohort 1) or R/R PMBL, mantle cell lymphoma, t-iNHL or iNHL (cohort 2), at least 1 month ago

• Patients who are not, at least in partial metabolic response from 1 month after CAR T-cells infusion (i.e no metabolic response or first metabolic progressive disease or first relapse from 1 month after CAR T-cells infusion)

• First metabolic progression, first relapse or no metabolic response after CAR T-cells infusion must be confirmed by PET-CT central review for enrollment

• DLBCL with demonstrated lymphoma cells-expressing CD20 at relapse post CAR T-cells as demonstrated by biopsy before enrollment (cohort 1 only)

• Aged 18 years or more with no upper age limit

• ECOG performance status 0 or 1

• Bi-dimensionally measurable disease defined by at least one single node or tumor lesion \> 1.5 cm assessed by CT scan, or PET-CT with at least one hypermetabolic lesion

• No persistant CAR-T neurotoxicity symptoms or previous experience during CAR T-cells therapy of neurotoxicity grade \> 3

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

⁃ Adequate liver function: Total bilirubin ≤ 1.5 x ULN; Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ≤ 3 x ULN Note: Patients with documented history of Gilbert's Syndrome and in whom total bilirubin elevations are accompanied by elevated indirect bilirubin are eligible)

⁃ Adequate hematological function: Neutrophil count of ≥ 1.0 G/L; Platelet count of ≥ 50 G/L (and platelet transfusion free within 14 days prior to administration of obinutuzumab); Hemoglobin (Hb) ≥ 8.0 g/dL (transfusion free within 21 days prior to administration of obinutuzumab) Note: patients who do not meet the above hematologic criteria, due to extensive tumor involvement in the marrow may be enrolled into the trial after the demonstration of involvement and consultation with the LYSARC. Please consult the LYSARC on the need for transfusion support within 21 days of obinutuzumab

⁃ Adequate renal function: creatinine clearance (CrCl) calculated by MDRD/cockcroft -Gault formula of ≥ 30 mL/min

⁃ Negative serum or urinary pregnancy test within 7 days prior to study treatment in women of childbearing potential

⁃ Negative serologic or PCR test results for acute or chronic HBV infection Note: Patients whose HBV infection status cannot be determined by serologic test results must be negative for HBV by PCR to be eligible for study participation

⁃ Negative test results for HCV and HIV Note: Patients who are positive for HCV antibody must be negative for HCV by PCR to be eligible for study participation

⁃ Patients must agree to either remain completely abstinent or to use two effective contraceptive methods\* until:

∙ If the patient is a male: at least 3 months after pre-treatment with obinutuzumab or 2 months after the last dose of glofitamab, whichever is longer, Men must refrain from donating sperm during this same period

‣ If patient is a female of childbearing potential: until at least 18 months after pre-treatment with obinutuzumab or 2 months after the last dose of glofitamab, whichever is longer

⁃ Patient must be willing and able to comply with protocol-mandated hospitalization upon administration of the first dose of glofitamab. Patient must also be willing to comply with all study-related procedures.

⁃ Signed written informed consent

⁃ Life expectancy ≥ 3 months

⁃ Patient covered by any social security system

⁃ Patient who understands and speaks one of the country official languages