Richter syndrome of chronic lymphocytic leukemia MedDRA version: 20.0 Level: PT Classification code 10058728 Term: Richter's syndrome System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Conditions
Interventions
Product Name: Gazyvaro
Product Code: [Obinutuzumab]
Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: Obinutuzumab
Current Sponsor code: Obinutuzumab
Concentration unit:
Sponsors
AZIENDA OSPEDALIERA AO OSPEDALE NIGUARDA CA' GRANDA
Eligibility
Sex/Gender
All
Inclusion 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 =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 = 50 mL/min based on Cockcroft-Gault formula; - Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =65 years) yes F.1.3.1 Number of subjects for this age range 1
Exclusion criteria
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: a) Patients with curatively treated basal or squamous cell carcinoma or stage 1 melanoma of the skin or in situ carcinoma of the cervix b) 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. c) 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. History of human immunodeficiency virus (HIV) or active hepatitis C virus (HCV) or active hepatitis B virus (HBV). 21. Major surgery within 4 weeks of first dose of study drug. 22. Any life-threatening illness, medical condition, or organ system dysfunction that, inthe investigator's opinion, could compromise the subject's safety or put the study outcomes at undue risk. 23. Patients with infections requiring IV treatment (Grade 3 or 4) within the last 2 months prior to enrolment.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Efficacy of the combination venetoclax, obinutuzumab and atezolizumab in terms of Overall Response Rate (ORR).;Secondary Objective: •Safety and tolerability of the combination venetoclax, obinutuzumab and atezolizumab •Efficacy of the combination venetoclax, obinutuzumab and atezolizumab in terms of: - Complete response rate, defined as CRR - Duration of response DoR - Progression free survival (PFS) - Overall survival (OS);Primary end point(s): The treatment will be considered effective if the combination enables the achievement of a minimum of 67% ORR at the end of the sixth cycle. Patients will be evaluated according to Lugano Criteria for aggressive lymphomas (Cheson et al. JCO, 2014). Residual underlying CLL may persist in node and/or marrow and still qualify as CR, denoting complete response of RT to treatment (Hallek M et al. IwCLL Criteria Blood 2008).;Timepoint(s) of evaluation of this end point: First 6 cycles of therapy (126 days from screening). | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Incidence of adverse events (AE) and serious adverse event (SAE) as measured per NCI-CTCAE v4.0; significant laboratory abnormality and dose tolerability (dose modifications and discontinuation).; Assessment of the efficacy of the combination of obinutuzumab, atezolizumab and venetoclax with respect to: - Complete Remission Rate (CRR) - Duration of Response (DoR) - Progression Free Survival (PFS) - Overall Survival (OS).; Exploratory endpoints: a) Correlation between response rate and PFS with the following biomarkers: PD1/PD-l1 expression, clonal relationship between CLL and DLBCL-type RS, TP53 status, MYC status, BCL2 status, CDKN2A status, mutational profile, microenvironment immuneprofile by gene expression, cell of origin by gene expression b) Comprehensive MRD monitoring based on combined flow cytometry and ultra-deep next generation sequencing (NGS) of disease markers (i.e. immunoglobulin gene rearrangement and gene mutations) in genomic DNA from blood, and in cell free DNA from plasma is more accurate than flow cytometry and translates into a better prediction of remission duration after treatment discontinuation c) Determination of the immunomodulatory effects exerted by the combination of venetoclax and anti-PDL1 inhibitor on: - The percentage and the absolute number of conventional T lymphocytes (CD3+/CD4+ and CD3+/CD8+ cells) and their subset distribution (i.e. naïve/central memory/effector memory/TEMRA) - The expression of marker of functional exhaustion and immune checkpoints on T lymphocytes (e.g. PD-1, CTLA4) - The Th1/Th2 polarization of the CD4+ T-cell population - The percentage and the absolute number of Regulatory T cells (Tregs) (CD4+/CD25hi/CD127low/FOXP3+) - The percentage and the absolute number of NK and NK-T cell compartments and the activation of NK cells (analyzing the expression of CD16, CD56, NKG2D, TIM3, TIGIT and CD96) - The percentage and the absolute number of monocytes (CD14+ cells) - Serum cytokine (CK) | — |
Countries
Italy, Switzerland
Contacts
Public ContactUO EMATOLOGIA ADULTI - Dott.ssa Ted
ASST NIGUARDA
Outcome results
None listed