ObinutuzuMab AtezOlizumab and VenetocLax in RichTer transfOrmation

• Status: Recruiting
• Trial end date: 2026-12-01
• Target enrollment: 0
• Participant gender: All

Summary

This study is a multicenter, open-label, uncontrolled, phase II trial aimed to establish the safety and tolerability of venetoclax, atezolizumab and obinutuzumab combination in Richter Transformation of CLL.

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

Details

• Lead Sponsor: Niguarda Hospital
• Treatments: Antibodies, Monoclonal; Atezolizumab; Obinutuzumab; Venetoclax

Criteria

Inclusion Criteria:

1. Ability to understand and the willingness to sign a written informed consent document

2. Signed Informed Consent

3. Confirmed diagnosis of chronic lymphocytic leukemia or small lymphocytic lymphoma as IW-CLL 2008 criteria (Hallek et al, 2008) with biopsy proven transformation to diffuse large B cell lymphoma (DLBCL), consistent with Richter's Syndrome

4. Age greater than or equal to 18 years

5. ECOG performance status <= 2

6. Patients must meet the following hematologic criteria at screening, unless they have significant bone marrow involvement of their malignancy confirmed on biopsy:

• Absolute neutrophil count >=1000 cells/mm3 (1.0 x 10^9/L).

• Platelet count >= 50,000 cells/mm3 (50 x 10^9/L) within 7 days of screening

• Total hemoglobin > 9 g/dL (without transfusion support, unless anemia is due to marrow involvement of CLL)

7. Subject must have adequate coagulation, renal, and hepatic function, per laboratory reference range at screening as follows:

• Activated partial thromboplastin time (aPTT) and International normalized ratio (INR) > 1.5 x ULN for patients not receiving therapeutic anticoagulation;

• Creatinine <= 1.5 x ULN or creatinine clearance >= 50 mL/min based on Cockcroft-Gault formula;

• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) <= 2.5 × ULN;

• Bilirubin <= 1.5 × ULN;

8. Subjects with Gilbert's Syndrome or resolving autoimmunohemolytic anemia may have a bilirubin up to 3.0 × ULN and are still eligible

9. Negative pregnancy tests as verified by the investigator prior to starting any treatment.

Exclusion Criteria:

1. Prior treatment for Richter transformation.

2. Prior treatment with obinutuzumab anti PD-1 or PDL-1 antibodies.

3. Prior treatment with venetoclax.

4. Hypersensitivity to obinutuzumab, venetoclax or atezolizumab or their formulation excipients.

5. Patients with the Hodgkin variant transformation of CLL.

6. Prolymphocytic transformation.

7. Patients with a previous history of indolent B cell malignancies other than CLL.

8. History of other malignancy other than CLL and Richter syndrome that could affect compliance with the protocol or interpretation of results with the exception of:

1. Patients with curatively treated basal or squamous cell carcinoma or stage 1 melanoma of the skin or in situ carcinoma of the cervix

2. Patients with a malignancy that has been treated with surgery alone with curative intent. Individuals in documented remission without treatment for > 2 years prior to enrollment may be included at the discretion of the Sponsor-Investigator.

3. Low-risk prostate cancer on active surveillance.

9. Evidence of significant, uncontrolled concomitant diseases that could affect compliance with the protocol or interpretation of results or that could increase risk to the patient, including renal disease that would preclude chemotherapy administration or pulmonary disease (including obstructive pulmonary disease and history of bronchospasm).

10. Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection (excluding fungal infections of nail beds) at study enrollment, or any major episode of infection requiring treatment with IV antibiotics or hospitalization (relating to the completion of the course of antibiotics) within 4 weeks prior to Cycle1, Day1.

11. Clinically significant history of liver disease, including autoimmune hepatitis, current alcohol abuse, or cirrhosis.

12. Presence of positive PCR for hepatitis B, hepatitis C or positive hepatitis B surface antigen.

13. Patients with uncontrolled autoimmune hemolytic anemia or immune thrombocytopenia.

14. History of active autoimmune disease.

15. History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis per chest CT scan at screening. History of radiation pneumonitis in the radiation field (fibrosis) is allowed.

16. Concurrent systemic immunosuppressant therapy within 28 days of the first dose of study drug.

17. Corticosteroids are allowed, but must be dosed at prednisone 30 mg (or equivalent) or lower prior to the start of chemotherapy.

18. Vaccinated with live, attenuated vaccines within 4 weeks of first dose of study drug.

19. Known bleeding disorders (eg, von Willebrand's disease) or hemophilia.

20. Requires anticoagulation with vitamin K antagonists (e.g. phenprocoumon, warfarin)

21. History of human immunodeficiency virus (HIV) or active hepatitis C virus (HCV) or active hepatitis B virus (HBV).

22. Major surgery within 4 weeks of first dose of study drug.

23. Any life-threatening illness, medical condition, or organ system dysfunction that, in the investigator's opinion, could compromise the subject's safety or put the study outcomes at undue risk.

24. Patients with infections requiring IV treatment (Grade 3 or 4) within the last 2 months prior to enrolment.