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.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
20
Undergo tumor biopsy
Undergo blood specimen collection
Undergo bone marrow biopsy and/or aspiration
Undergo PET/CT
Given IV
Given IV
Given PO
Given IV
Given IV
Undergo apheresis
Undergo PET/CT
City of Hope Medical Center
Duarte, California, United States
RECRUITINGMemorial Sloan Kettering Cancer Center
New York, New York, United States
RECRUITINGComplete Response (CR)
After cycle 3, the rate and associated 95% binomial exact confidence interval will be estimated.
Time frame: Up to 2 years
Unacceptable Toxicity (UT)
Toxicities will be summarized by organ, severity, time of onset and characteristic. UT will be described individually and summarized by count and rate/percentage.
Time frame: Up to 28 days post CAR T cell infusion
Toxicity
Toxicities will be summarized by organ, severity, time of onset and characteristic. Assessed per ASTCT Consensus Criteria
Time frame: Up to 2 years
Best Complete Response (CR)
Defined as the proportion of patients that achieve CR at any time from start of protocol treatment to any disease progression or start of new anticancer treatment.
Time frame: Up to 2 years
Overall Response Rate (ORR)
Defined as the proportion of patients that achieve a best response of CR or partial response (PR) from start of protocol treatment prior to any disease progression or start of new anticancer treatment.
Time frame: Up to 2 years
Duration of Response (DOR)
Defined as the time from the first documented CR or PR through disease relapse, progression or death. Data for those patients without CR/ PR, disease progression, relapse or death will be captured at last follow up or start of non-protocol anticancer therapy. Those patients that do not achieve CR/PR will be excluded. Kaplan-Meier product limit method with log-log transformation for the confidence interval will be used to estimate the DOR.
Time frame: Up to 2 years
Minimal Residual Disease (MRD)
Evaluated in the peripheral blood and bone marrow using ClonoSEQ analysis. MRD at baseline will be summarized by descriptive analysis.
Time frame: Up to 2 years
Progression Free Survival (PFS)
Data for patients without disease relapse/ progression or death will be collected at the last follow-up or at start of non-protocol anticancer therapy. Kaplan-Meier product limit method with log-log transformation for the confidence interval will be used to estimate the PFS.
Time frame: From start of protocol treatment through disease relapse/ progression or death, assessed up to 2 years
Overall Survival (OS)
Data for alive patients will be collected at last follow up. Kaplan-Meier product limit method with log-log transformation for the confidence interval will be used to estimate the OS.
Time frame: From the start of protocol treatment through death due to any cause, assessed up to 2 years
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