Evaluation of Treatment by Glofitamab in Combination With Rituximab or Obinutuzumab Plus CHOP in Patients With RIchter Syndrome

Study design :

Open label, multicenter phase 2 trial

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).

Primary objective:

The primary objective is to determine the objective response regarding the RS to 6 cycles of R/G-CHOP + glofitamab in patients with RS.

Secondary objectives:

The secondary objectives are to investigate the safety and toxicity of 6 cycles R/G-CHOP + glofitamab, the response to 6 cycles of R/G-CHOP + glofitamab and the patient outcome.

Sample size : 40 patients Length of study: Inclusion period: 18 months Treatment duration: 6 months (24 weeks) Follow-up period: 12 months Duration of the study: 36 months

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 Evaluation will be performed after C4 and C6 (see 6.2.3. and 6.2.4.). Responding patients with response (CR or PR according to Cheson IWG 2014 Lugano Classification (i.e. Deauville scale 1-3)) after C6 will receive two more infusions of glofitamab (day 8 of C7 and C8).

Cycle 7 and 8:

Cycle 7 and 8 consist of 2 infusions of glofitamab only at D8C7 and D8C8:

Glofitamab : 30 mg IV Day 8

Study procedures:

Screening period :

Assessments may be done up to 28 days before the treatment start and will include:

Clinical assessments Medical history including demographics, previous and current diseases, medications included previous CLL treatment(s) Physical examination (B symptoms, weight, height), tumor lesion assessment including peripheral nodes location and two dimensional diameters, vital signs (pulse, blood pressure, body temperature) Binet staging (appendix 3) ECOG performance status (appendix 4) Ann Arbor staging (appendix 5) Assessment of the international Prognostic Index (IPI) (appendix 6) Determination of the CIRS score (appendix 7) Standard laboratory assessments Hematology Biochemistry Other exams HIV 1-2, HBV and HCV serology (Ag HBs, Ac anti-HBs, Ac anti-HBc, Ac anti-VHC), SARS-COV-2 serology and PCR Pregnancy test (beta-HCG) for women of child-bearing potential Coagulation test (fibrinogen, APTT, PT) Specific assessments Immunophenotyping (including CD38) of peripheral lymphocytes and Matutes RMH score Karyotype and 4-color FISH analysis for: 17p13 deletion, 11q22 deletion, 13q14 deletion and trisomy 12 of either blood or marrow CLL cells IGHV mutational status on CLL samples (at baseline or before). IGHV status should also be performed on the Richter specimen DNA in order to determine the clonal relationship between RS and CLL.

TP53 gene sequencing according to ERIC recommendation (on CLL cells). Bone marrow biopsy Imaging exams Whole-body CT scan (thorax, abdomen, pelvis) and measurement in two perpendicular dimensions and response assessments according to the revised Lugano criteria (appendix 1) Whole body PET-scan with SUV measurement and response assessments according to the revised Lugano criteria (appendix 1).

Other exams 12-lead ECG Assessment of left ventricular ejection function by either cardiac ultrasound or isotopic ventriculography

Treatment period :

Before each cycle (R/G-CHOP)

Clinical assessment:

Physical examination Concomitant medications Adverse events, serious adverse events and adverse events of special interest Hematology Biochemistry Before each cycle (Glofitamab alone)

Clinical assessment:

Vital signs (pulse, blood pressure, body temperature) Concomitant medications Adverse events, serious adverse events and adverse events of special interest Hematology Biochemistry Electrolytes (sodium, potassium, calcium, phosphore) Total protein, glycemia, urea, uric acid, serum creatinine and creatinine clearance (Cockroft and Gault formula) Bilirubin, ASAT, ALAT, GGT, alkaline phosphatases LDH C-reactive protein After 4 cycles of R/G-CHOP + glofitamab (W12) and after 6 cycles of R/G-CHOP + glofitamab (W18)

Clinical assessment:

Physical examination (B symptoms, weight, height, ECOG performance status), tumor lesion assessment including peripheral nodes location and two dimensional diameters Vital signs (pulse, blood pressure, body temperature) Writing test (C6 only) Concomitant medications Adverse events, serious adverse events and adverse events of special interest Hematology Biochemistry

Imaging exams Whole-Body CT scan Whole body PET-scan with suv measurement and response assessment according to the revised Lugano criteria (appendix 1) will also be performed.

Only after 6 cycles of R/G-CHOP + glofitamab (W18) Bone marrow biopsy only if CR criteria obtained in both CT scan and PET. Follow up assessments The follow-up will be performed every 3 months for 12 months (FU3, FU6, FU9, FU12) after the end of last treatment by glofitamab (C8D8) or if patient stopped treatment prematurely without initiate a new treatment.

End of treatment (EOT):

A visit will be performed within 30 days after the last administration of study treatment for patient stop treatment prematurely and Withdrawn of the study A discontinuation/withdrawal form will be sent to the Filo secretary and head of project.

For patient continue follow up visits no EOT is required.

End of study (EOS):

The end of study becomes effective after the end of last study visit of last patient enrolled and performed the FU12 visit.

The end of study visit corresponds to the last follow-up visit (FU12). For patient withdraw during follow up period, no end of study visit is required.

Observational study:

For all patient without withdrawn at FU12 visit (see paragraph 9.2 definition of withdrawal):

After this last study visit and if patient consents, the Survival date will be collected every year in the eCRF (Survival date and/or event date form) until death, for analyse the survival:

Date of last news. Patient status: alive/death/lost of sight Patient response. Initiation of new treatment.

Investigational product:

Obinutuzumab (Gazyvaro®) Obinutuzumab is a humanized glycoengineered type II anti-CD20 monoclonal antibody that recognizes the CD20 antigen present on normal and malignant B cells and is being developed for the treatment of hematological malignancies including NHL and CLL.

Glofitamab:

Glofitamab is a "2:1" T-cell bispecific humanized monoclonal antibody that binds to human CD20 on B cells through two fragment antigen-binding domains, and to the human CD3 epsilon subunit (CD3e) of the T-receptor (TCR) complex on T cells through a single Fab domain.

Safety :

Patient safety will be assessed based on clinical and laboratory evaluations, physical examinations, vital signs, and monitoring of adverse events (AEs).