Venetoclax, Rituximab and Nivolumab Combination in Patients With Richter's Transformation (RT) Arising From Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL): A Phase II Study With Safety Run-In
Overview
- Phase
- Phase 2
- Intervention
- Biopsy
- Conditions
- Recurrent Transformed Chronic Lymphocytic Leukemia
- Sponsor
- Northwestern University
- Locations
- 1
- Primary Endpoint
- Overall response rate
- Status
- Withdrawn
- Last Updated
- 2 years ago
Overview
Brief Summary
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.
Detailed Description
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.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Patients must have a confirmed diagnosis of one of Richter's transformation (to either diffuse large B cell lymphoma (DLBCL) or Hodgkin's lymphoma) with preceding CLL/SLL
- •Richter's transformation refers to development of aggressive lymphoma (most commonly diffuse large B cell lymphoma (DLBCL), and less commonly Hodgkin's lymphoma) in a patient who has a pre-existing diagnosis of CLL/SLL. A pathologic diagnosis of DLBCL or Hodgkin's lymphoma in the setting of preceding CLL/SLL is required
- •Patients with Richter's transformation arising from CLL/SLL may be newly diagnosed or have relapsed or progressed after prior treatment. Patients with newly diagnosed Richter transformation are eligible only if the treating physician believes they are not good candidates for standard immunochemotherapy or chemotherapy
- •All patients must have measurable disease as defined by Lugano criteria 2014
- •Patients must be age ≥ 18 years
- •Patients must exhibit a/an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
- •Absolute neutrophil count ≥ 1,000/mcL (independent of growth factor support for ≥ 14 days) (within 14 days prior to registration)
- •Platelets ≥ 30,000/mcl (independent of transfusion for ≥ 14 days) (within 14 days prior to registration)
- •Hemoglobin ≥ 8 g/dL (within 14 days prior to registration)
- •Note: patients must be able to maintain this level without transfusion
Exclusion Criteria
- •Patients who have received prior nivolumab for treatment of Richter's transformation, or other PD-1/PD-L1 for the treatment of any indication.
- •Note: Prior anti-CD-20 antibody treatment is allowed with ≥ 14 day washout period. Prior treatment with nivolumab is permissible if for a different disease indication. In such cases nivolumab must have been discontinued ≥ 3 months prior to registration
- •Patients who have a history of life-threatening adverse reactions attributed to compounds of similar chemical or biologic composition to venetoclax, nivolumab, or rituximab
- •Patients who are refractory to venetoclax (defined by disease progression while on venetoclax or within 3 months of discontinuing venetoclax)
- •Patients who have had prior chimeric antigen receptor-modified T-cell (CAR-T) therapy within the 45 days prior to registration or with any remaining CAR-T related cytokine-release syndrome or neurotoxicity
- •Patients who have adverse events due to agents administered ≥ 30 days prior to registration that have not recovered to ≤ grade 2
- •Patients who have had chemotherapy, radiotherapy or immunotherapy ≤ 14 days prior to registration
- •Patients receiving any other investigational agents within ≤ 30 days or 5 half-lives prior to registration, whichever is shorter
- •Patients who have received B-cell receptor pathway inhibitor (such as ibrutinib or idelalisib) ≤ 3 days prior to receiving study treatment
- •Patients who have undergone an autologous stem cell transplant ≤ 120 days prior to registration
Arms & Interventions
Treatment (venetoclax, rituximab, nivolumab)
Patients receive venetoclax PO QD on days 1-28, nivolumab 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 PET/CT and CT or MRI during screening and on the trial.
Intervention: Biopsy
Treatment (venetoclax, rituximab, nivolumab)
Patients receive venetoclax PO QD on days 1-28, nivolumab 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 PET/CT and CT or MRI during screening and on the trial.
Intervention: Biospecimen Collection
Treatment (venetoclax, rituximab, nivolumab)
Patients receive venetoclax PO QD on days 1-28, nivolumab 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 PET/CT and CT or MRI during screening and on the trial.
Intervention: Bone Marrow Biopsy
Treatment (venetoclax, rituximab, nivolumab)
Patients receive venetoclax PO QD on days 1-28, nivolumab 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 PET/CT and CT or MRI during screening and on the trial.
Intervention: Computed Tomography
Treatment (venetoclax, rituximab, nivolumab)
Patients receive venetoclax PO QD on days 1-28, nivolumab 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 PET/CT and CT or MRI during screening and on the trial.
Intervention: Magnetic Resonance Imaging
Treatment (venetoclax, rituximab, nivolumab)
Patients receive venetoclax PO QD on days 1-28, nivolumab 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 PET/CT and CT or MRI during screening and on the trial.
Intervention: Nivolumab
Treatment (venetoclax, rituximab, nivolumab)
Patients receive venetoclax PO QD on days 1-28, nivolumab 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 PET/CT and CT or MRI during screening and on the trial.
Intervention: Positron Emission Tomography
Treatment (venetoclax, rituximab, nivolumab)
Patients receive venetoclax PO QD on days 1-28, nivolumab 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 PET/CT and CT or MRI during screening and on the trial.
Intervention: Rituximab
Treatment (venetoclax, rituximab, nivolumab)
Patients receive venetoclax PO QD on days 1-28, nivolumab 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 PET/CT and CT or MRI during screening and on the trial.
Intervention: Venetoclax
Outcomes
Primary Outcomes
Overall response rate
Time Frame: Up to 5 years
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.
Best response rate
Time Frame: Up to 5 years
Will be assessed using iwCLL and Lugano 2014 criteria for RT patients. Will be calculated using proportions and exact 95% binomial confidence intervals.
Minimal residual disease (MRD) rate
Time Frame: Up to 5 years
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.
Secondary Outcomes
- Duration of response(Up to 5 years)
- Overall survival(Up to 5 years)
- Prognostic markers and biomarkers(Up to 5 years)
- Progression-free survival(Up to 5 years)
- Incidence of adverse events(Up to 100 days after last dose of study treatment)