A Phase 2 Study Evaluating the Bispecific CD3xCD20 Antibody GLOfitamab in Combination With Rituximab or Obinutuzumab Plus Cyclophosphamide, Doxorubicin, Vincristine and Prednisone (CHOP) in Patients With RIchter Syndrome as Frontline therapY
This is a national clinical trial, multicentric (28 centers), non-randomized phase 2 study. Population: Patients with previously untreated Richter's syndrome (RS), defined as the occurrence of an aggressive lymphoma (of diffuse large B-cell lymphoma histology) in a patient with chronic lymphocytic leukemia (CLL). Study treatment: The duration of each cycle is 21 days. Cycle 1: Participants will receive standard of care doses of R-CHOP in cycle 1 as follows: * Rituximab 375 mg/m² IV Day 1 * Cyclophosphamide 750 mg/m² IV Day 1 * Doxorubicin 50 mg/m² IV Day 1 * Vincristine 1.4 mg/m² \[capped at 2.0 mg\] IV Day 1 * Prednisone 60 mg/m2 per day PO Day 1-5 Cycle 2: In order to minimize cytokine release syndrome (CRS), participants will then receive G-CHOP as cycle 2 (with obinutuzumab) and glofitamab: * Obinutuzumab 1000 mg single dose IV Day 1 * Cyclophosphamide 750 mg/m² IV Day 1 * Doxorubicin 50 mg/m² IV Day 1 * Vincristine 1.4 mg/m² \[capped at 2.0 mg\] IV Day 1 * Prednisone 60 mg/m2 per day PO Day 1-5 * Glofitamab : administered intravenously (IV) as a step-up dose on Days 8 (2.5 mg) and 15 (10 mg) Cycle 3-6: Participants will receive standard of care doses of R-CHOP and Glofitamab as follows: * Rituximab 375 mg/m² IV Day 1 * Cyclophosphamide 750 mg/m² IV Day 1 * Doxorubicin 50 mg/m² IV Day 1 * Vincristine 1.4 mg/m² \[capped at 2.0 mg\] IV Day 1 * Prednisone 60 mg/m2 per day PO Day 1-5 * Glofitamab : 30 mg IV Day 8 Cycle 7 and 8 (only for patient in Complete Response or Partial response after Cycle 6): Cycle 7 and 8 consist of 2 infusions of glofitamab only at D8C7 and D8C8: ● Glofitamab : 30 mg IV Day 8 Primary endpoint Percentage of participants with a complete response as assessed by the investigator using the Cheson IWG 2014 Lugano Classification (i.e. Deauville scale 1-3) after 6 cycles of R/G-CHOP + glofitamab or at permanent treatment discontinuation. End of treatment is defined as after 6 cycles of R/G-CHOP + glofitamab. Permanent treatment discontinuation is defined as the discontinuation of all treatments (R/G-CHOP, glofitamab).
• Confirmed diagnosis of chronic lymphocytic leukemia or small lymphocytic lymphoma according to the revised iwCLL criteria with biopsy proven transformation to CD20 positive diffuse large B-cell lymphoma, consistent with RS according to the 2016 WHO classification
• A fresh or archival tissue biopsy is mandatory
• Previous therapy for CLL is allowed (but no prior therapy for RS)
• Age greater than or equal to 18 years and less or equal to 80 years
• ECOG performance status 0-2
• Participants must have at least one measurable target lesion (≥ 1.5 cm) in its largest dimension by computed tomography (CT) scan. Measurable disease, defined as at least one bi-dimensionally measurable nodal or tumor lesion, defined as \> 1.5 cm in its longest dimension or PET-CT with at least one hypermetabolic lesion. Patients without measurable disease but with proven bone marrow infiltration by the RS are eligible.
• Patients must meet the following hematologic criteria at screening, unless they have significant bone marrow involvement of either CLL or RS cells confirmed on biopsy: absolute neutrophil count ≥ 1.5 G/L, hemoglobin \>10 g/dL, and platelet count ≥75 G/L independent of transfusion within 7 days of screening
• Subject must have adequate coagulation tests: Prothrombin Time \> 50%, Fibrinogen \> 1 g/L
• Adequate liver function: Total bilirubin ≤ 1.5 x ULN; Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ≤ 3 x ULN
⁃ Adequate left ventricular ejection function (\> 50 %)
⁃ Adequate renal function: creatinine clearance calculated by MDRD/Cockcroft-Gault formula of ≥ 40 mL/min
⁃ Negative serologic or PCR test results for acute or chronic HBV infection
⁃ Negative test results for HCV and HIV (Patients who are positive for HCV antibody must be negative for HCV by PCR to be eligible for study participation)
⁃ Prior vaccination to the SARS-Cov-2 virus and and SARS-CoV-2 PCR testing and negative result before study treatment administration at each treatment cycle
⁃ Negative serum or urinary pregnancy test within 7 days prior to study treatment in women of childbearing potential. 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 RCHOP 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 RCHOP or 2 months after the last dose of glofitamab, whichever is longer
⁃ Ability to understand and the willingness to sign a written informed consent document. 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
⁃ Patient covered by any social security system