Venetoclax, Rituximab and Nivolumab in Combination for the Treatment of Richter's Transformation Arising From Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

Richter Syndrome Clinical Trial

Official title: 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

Status Withdrawn

Clinical Trial 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.

Clinical Trial 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. ;

Related Conditions & MeSH terms

• Leukemia
• Leukemia, Lymphocytic, Chronic, B-Cell
• Leukemia, Lymphoid
• Lymphoma
• Lymphoma, B-Cell
• Lymphoma, Large B-Cell, Diffuse
• Recurrent Transformed Chronic Lymphocytic Leukemia
• Refractory Transformed Chronic Lymphocytic Leukemia
• Richter Syndrome
• Transformed Chronic Lymphocytic Leukemia to Diffuse Large B-Cell Lymphoma
• Transformed Small Lymphocytic Lymphoma to Diffuse Large B-Cell Lymphoma

• NCT number: NCT06247540
• Study type: Interventional
• Source: Northwestern University
• Status: Withdrawn
• Phase: Phase 2
• Start date: March 29, 2024
• Completion date: December 29, 2031