This phase II trial tests how well venetoclax, rituximab and nivolumab works in treating patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) with Richter's transformation. Richter's transformation can be described as the development of an aggressive lymphoma in the setting of underlying CLL/SLL that has a very poor prognosis with conventional therapies and represents a significant unmet medical need. Venetoclax is in a class of medications called B-cell lymphoma-2 (BCL-2) inhibitors. It may stop the growth of cancer cells by blocking BCL-2, a protein needed for cancer cell survival. Immunotherapy with monoclonal antibodies, such as rituximab and nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of cancer cells to grow and spread. Giving venetoclax, rituximab and nivolumab together may work better than the conventional intensive immunochemotherapy to improve disease control in patients with Richter's transformation arising from CLL/SLL.
PRIMARY OBJECTIVE: I. To determine the preliminary efficacy in terms of overall response rate (ORR) per Lugano criteria with venetoclax, nivolumab, and rituximab combination in patients with Richter's transformation. SECONDARY OBJECTIVES: I. To determine the safety and tolerability of venetoclax, nivolumab, and rituximab combination in Richter's transformation (RT) using Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v 5.0). II. To determine preliminary efficacy in terms of complete response (CR) with venetoclax, nivolumab, and rituximab combination in patients with RT. III. To determine the preliminary efficacy in terms of minimal residual disease (MRD) negativity rate with venetoclax, nivolumab, and rituximab combination in patients with RT. IV. To determine the preliminary efficacy in terms of progression free survival (PFS) at 12 months with venetoclax, nivolumab, and rituximab combination in patients with RT. V. To determine the preliminary efficacy in terms of overall survival (OS) with venetoclax, nivolumab, and rituximab combination in patients with RT. EXPLORATORY OBJECTIVES: I. The study team will study various prognostic markers and biomarkers and correlate them with clinical response: Ia. MRD status in bone marrow and peripheral blood; Ib. CLL prognostic markers, cytogenetics abnormalities by fluorescence in situ hybridization (FISH), IgVH mutation status, and TP53 mutation status; Ic. PD-L1 and PD-1 expression by immunohistochemistry (IHC), either in lymph node tissue samples or bone marrow; Id. T-cell subsets in the blood and tissue biopsy. EXPLORATORY STUDIES OBJECTIVES: I. To determine the clinical and pathological factors impacting clinical response to the rituximab-nivolumab-venetoclax combination therapy. II. To study the role of PD-1 blockade in RT. III. To determine the role of bone marrow and peripheral blood MRD in the RT study population. OUTLINE: This is a dose-escalation study of venetoclax. Patients receive venetoclax orally (PO) once daily (QD) on days 1-28, nivolumab intravenously (IV) over 30 minutes on days 2 and 15 of cycles 1-4 and day 1 of each subsequent cycle, and rituximab IV on day 2 of cycle 1 and day 1 of cycles 2-6. Treatment repeats every 28 days up to 6 cycles in the absence of disease progression or unacceptable toxicity. After the completion of 6 cycles, rituximab is discontinued and patients receive venetoclax PO QD on days 1-28 and nivolumab IV over 30 minutes on day 1 of each cycle. Treatment repeats every 28 days for up to 2 years total therapy in the absence of disease progression or unacceptable toxicity. Patients undergo tissue biopsy during screening. Patients undergo a bone marrow biopsy and blood sample collection as well as positron emission tomography (PET)/computed tomography (CT) and CT or magnetic resonance imaging (MRI) during screening and on the trial. After completion of study treatment, patients are followed up at 30 days and every 90 days for 5 years from the start of treatment.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Undergo tissue biopsy
Undergo blood sample collection
Undergo bone marrow biopsy
Undergo PET/CT, CT
Undergo MRI
Receive IV
Undergo PET/CT
Receive IV
Receive PO
Northwestern University
Chicago, Illinois, United States
Overall response rate
Will be assessed using International Workshop on Chronic Lymphocytic Leukemia (iwCLL) and Lugano 2014 criteria for Richter's transformation (RT) patients. Will be calculated using proportions and exact 95% binomial confidence intervals.
Time frame: Up to 5 years
Best response rate
Will be assessed using iwCLL and Lugano 2014 criteria for RT patients. Will be calculated using proportions and exact 95% binomial confidence intervals.
Time frame: Up to 5 years
Minimal residual disease (MRD) rate
Will be assessed in chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) patients in the peripheral blood and bone marrow by flow cytometry, polymerase chain reaction (PCR) and/or sequencing. MRD negativity is defined as less than one CLL/SLL cell per 10,000 leukocytes (or below 10-4) on peripheral blood and/or bone marrow based flow cytometry and/or PCR based methods. Rate of MRD status will be defined as the proportion of patients who have MRD negativity status. Will be calculated using proportions and exact 95% binomial confidence intervals.
Time frame: Up to 5 years
Incidence of adverse events
Will calculate the number and percentage of toxicities by type, grade, severity and attribution. For all adverse events including laboratory values, physical examination characteristics, vital signs and electrocardiogram, Common Terminology Criteria for Adverse Events version 5.0 criteria will be used to classify the severity of the adverse event. All adverse events regardless of severity will be documented and will be summarized for regular review by the Cancer Center's Data and Safety Monitoring Committee.
Time frame: Up to 100 days after last dose of study treatment
Progression-free survival
Will be assessed using iwCLL and Lugano 2014 criteria for RT patients. Will be determined using a Kaplan-Meier curves with 5-year survival and 95% confidence interval reported
Time frame: Up to 5 years
Overall survival
Will be determined using a Kaplan-Meier curves with 5-year survival and 95% confidence interval reported
Time frame: Up to 5 years
Duration of response
Will be assessed using iwCLL and Lugano 2014 criteria for RT patients. Will be summarized using median and interquartile range.
Time frame: Up to 5 years
Prognostic markers and biomarkers
Will be correlated with clinical response using a Wilcoxon rank sum test. The statistical significance of individual markers, multivariate proportional hazards regression will be used to assess multiple markers simultaneously. Prognostic markers will be related to response using Fisher's exact test or the Wilcoxon rank sum test.
Time frame: Up to 5 years
This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.