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

• Status: Recruiting
• Trial end date: 2027-03-01
• Target enrollment: 0
• Participant gender: All

Summary

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).

• Phase: Phase 2
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: French Innovative Leukemia Organisation
• Collaborator: Hoffmann-La Roche
• Treatments: Obinutuzumab

Criteria

Inclusion Criteria:

1. 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

2. A fresh or archival tissue biopsy is mandatory

3. Previous therapy for CLL is allowed (but no prior therapy for RS)

4. Age greater than or equal to 18 years and less or equal to 80 years

5. ECOG performance status 0-2

6. 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.

7. 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

8. Subject must have adequate coagulation tests: Prothrombin Time > 50%, Fibrinogen > 1 g/L

9. Adequate liver function: Total bilirubin ≤ 1.5 x ULN; Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ≤ 3 x ULN

10. Adequate left ventricular ejection function (> 50 %)

11. Adequate renal function: creatinine clearance calculated by MDRD/Cockcroft-Gault formula of ≥ 40 mL/min

12. Negative serologic or PCR test results for acute or chronic HBV infection

13. 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)

14. 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

15. 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

16. 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

17. Signed written informed consent

18. Patient covered by any social security system

Exclusion Criteria:

1. Patients with the Hodgkin variant of RS

2. Patients with previously treated for RS

3. Current or past history or presence of clinically relevant disorder affecting the central nervous system (CNS)

4. Ineligible to CHOP full dose for any reason

5. Previous treatment with a bispecific antibody

6. Current or past history of DLBCL in the CNS (confirmed by CSF analysis)

7. Steroids treatment (> 1 mg/kg/d for one week) before inclusion

8. History of anaphylactic reactions to human, chimeric, or mouse monoclonal antibodies or to any components of the product.

9. Prior allogeneic HSCT

10. Patients with known acute infection or reactivation of a latent infection, whether bacterial, viral (including, but not limited to, EBV, cytomegalovirus (CMV), hepatitis B, hepatitis C, HIV and SARS-CoV-2), fungal, mycobacterial, or other pathogens (excluding fungal infections of nail beds) or any major episode of infection requiring hospitalization or treatment with IV antibiotics (for IV antibiotics this pertains to completion of last course of antibiotic treatment) within 4 weeks prior to the first study treatment.

11. History of other malignancies, except: i) malignancy treated with curative intent and with no recurrence over the last 3 years ii) adequately treated non-melanoma skin cancer without evidence of disease iii) adequately treated carcinoma in situ without evidence of disease

12. Prior solid organ transplantation

13. History of treatment-emergent immune-related adverse events associated with prior immunotherapeutic agents, as follows:

• Grade ≥ 3 adverse events with the exception of Grade 3 endocrinopathy managed with replacement therapy

• Grade 1-2 adverse events that did not resolve to baseline after treatment discontinuation

14. Current uncontrolled autoimmune disease*

15. History of human immunodeficiency virus

16. Hepatitis B or C seropositivity (unless clearly due to vaccination)

17. Pregnant or breastfeeding women

18. Unwilling or unable to participate in all required study evaluations and procedures.

19. Unable to understand the purpose and risks of the study and to provide a signed and dated informed consent form and authorization to use protected health information (in accordance with national and local subject privacy regulations)

20. Persons deprived of their liberty by judicial or administrative decision, persons subject to a legal protection measure (guardianship, curatorship, legal protection), persons under psychiatric care

21. Fertile male patients who cannot or do not wish to use an effective method of contraception, during and for 12 months after the final treatment used for the purposes of the study.

22. Patients with history of macrophage activation syndrome (MAS) / hemophagocytic lymphohistiocytosis (HLH)

23. LVEF < 50% as determined by echocardiography or multiple uptake gated acquisition (MUGA) scan, significant or extensive cardiovascular disease such as New York HeartAssociation Class III or IV cardiac disease or Objective Assessment Class C or D,myocardial infarction within the last 3 months, unstable arrhythmias, or unstable angina.

24. Abnormal screening laboratory values as defined as following: a) ALT (SGOT) and/or ALT (SGPT) and/or ALP ≥ 3 x upper limit of normal (ULN); b) Total bilirubin ≥ 1.5 x ULN, unless due to Gilbert's disease; c) Creatinine ≥ 2.0 x ULN or creatinine clearance < 40 mL/min (calculated).

25. Patient with history of confirmed progressive multifocal leukoencephalopathy (PML)

26. History of severe allergic or anaphylactic reactions to monoclonal antibody therapy (or recombinant antibody-related fusion proteins)

27. Any other diseases, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that would contraindicate the use of an investigational drug

28. Major surgery or significant traumatic injury < 28 days prior to the obinutuzumab infusion (excluding biopsies) or anticipation of the need for major surgery during study treatment

29. Administration of a live, attenuated vaccine within 4 weeks before obinutuzumab infusion

30. Treatment with another investigational agent or participating in another trial within 30 days prior to entering the study

31. Clinically significant history of liver disease or cirrhosis

32. Pregnant or breast-feeding or intending to become pregnant during the study

33. No affiliation to social security

34. Inability to comply with protocol mandated hospitalization and restrictions.