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

Launched by FRENCH INNOVATIVE LEUKEMIA ORGANISATION · Dec 29, 2023

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ClinConnect Summary

This clinical trial is looking at a new treatment approach for patients with Richter Syndrome, which is a type of aggressive lymphoma that can occur in people who have chronic lymphocytic leukemia (CLL). The study will evaluate the effectiveness of a combination of medications, including Glofitamab and either Rituximab or Obinutuzumab, along with standard chemotherapy (CHOP). This trial is open to adults aged 18 to 80 who have not received treatment for Richter Syndrome before, have a confirmed diagnosis of CLL, and meet certain health criteria.

Participants can expect to undergo several treatment cycles over a period of about six months. The treatments will be given through intravenous (IV) infusions, with a combination of medications during the first two cycles, followed by a standard treatment regimen in subsequent cycles. The main goal of the trial is to see how many participants achieve a complete response to the treatment, which means their lymphoma has significantly improved or disappeared. It's important for interested patients to discuss with their healthcare provider to see if they qualify and understand what participation entails.

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Eligibility 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.