Lisocabtagene Maraleucel, Nivolumab and Ibrutinib for the Treatment of Richter's Transformation

This phase II trial tests how well adding lisocabtagene maraleucel (liso-cel) to nivolumab and ibrutinib works in treating patients with Richter's transformation. Liso-cel is in a class of medications called autologous cellular immunotherapy, a type of medication prepared by using cells from patient's own blood. It works by causing the body's immune system (a group of cells, tissues, and organs that protects the body from attack by bacteria, viruses, cancer cells and other substances that cause disease) to fight the cancer cells. Nivolumab is in a class of medications called monoclonal antibodies. It works by helping the immune system to slow or stop the grown of cancer. Ibrutinib is in a class of medications called kinase inhibitors. It works by blocking the action of the abnormal protein that signals cancer cells to multiply. This helps stop the spread of cancer cells. Giving ibrutinib and nivolumab with Liso-cel may kill more cancer cells in patients with Richter's transformation.

PRIMARY OBJECTIVES: I. Evaluate the complete response (CR) rate after cycle 3 following lisocabtagene maraleucel (liso-cel) in combination with nivolumab and ibrutinib to treat patients with Richter's transformation (RT). II. Assess the Unacceptable toxicities (UT) rate within the first 28 days during cycle 1 following liso-cel infusion. (Safety lead-in only) SECONDARY OBJECTIVES: I. Assess the safety of liso-cel, nivolumab and ibrutinib to treat patients with RT. II. Estimate the best CR rate. III. Estimate the best overall response rate (ORR). IV. Estimate duration of response (DOR) at 2 years. V. Assess minimal residual disease (MRD) post liso-cel in participants with CLL at baseline. VI. Estimate progression free survival (PFS) at 2 years. VII. Estimate overall survival (OS) at 2 years. EXPLORATORY OBJECTIVES: I. Evaluate predictive biomarkers of response (genetic and immune) in peripheral blood, apheresis product, infusion product and circulating tumor (ct)DNA. II. Evaluate the ability of MRD assessed by ctDNA analysis to predict PFS. III. Evaluate changes in the lymph node microenvironment during nivolumab therapy, with an optional pre-CAR T cell infusion lymph node biopsy. IV. Evaluate the effect of liso-cel on CD19 expression on tumor cells at disease progression. OUTLINE: Patients receive ibrutinib orally (PO), nivolumab intravenously (IV), fludarabine IV, cyclophosphamide IV, and liso-cel IV on study. Patients also undergo apheresis, positron emission tomography (PET)/computed tomography (CT), collection of blood samples, and bone marrow biopsy on study. Patients may receive low-moderate intensity chemotherapy in combination with the study induction therapy per treating physician discretion with approval of study principal investigator.