This phase II trial tests how well zanubrutinib and lisocabtagene maraleucel (liso-cel) work together in treating patients with Richter's syndrome that has come back (recurrent) or does not respond to treatment (refractory). Richter's syndrome occurs when chronic lymphocytic leukemia and/or small lymphocytic leukemia transforms into an aggressive lymphoma, which is a cancer of the lymph nodes. Zanubrutinib is a class of medication called a kinase inhibitor. These drugs work by preventing the action of abnormal proteins that tell cancer cells to multiply, which helps stop the spread of cancer. Liso-cel is a type of treatment known as chimeric antigen receptor (CAR) T cell therapy. CAR T-cell therapy is a type of treatment in which a patient's T cells (a type of immune system cell) are changed in the laboratory so they will attack cancer cells. T cells are taken from a patient's blood. Then the gene for a special receptor that binds to a certain protein on the patient's cancer cells is added to the T cells in the laboratory. The special receptor is called a chimeric antigen receptor (CAR). Large numbers of the CAR T cells are grown in the laboratory and given to the patient by infusion for treatment of certain cancers. Giving zanubrutinib and liso-cell together may kill more cancer cells in patients with recurrent or refractory Richter's syndrome.
PRIMARY OBJECTIVE: I. To evaluate the efficacy of the combination of zanubrutinib and lisocabtagene maraleucel (liso-cel) for the treatment of Richter's syndrome (RS). SECONDARY OBJECTIVES: I. To describe the safety profile of the combination of zanubrutinib and liso-cel for RS. II. To evaluate duration of the efficacy of the combination of zanubrutinib and liso-cel for RS CORRELATIVE OBJECTIVES: I. Describe T-cell subsets before and after zanubrutinib initiation, as well as post liso-cel infusion. II. To describe the persistence of liso-cel. III. To describe the tumor microenvironment post liso-cel infusion at relapse. IV. Investigate the correlation between inflammatory cytokines and measures of inflammation and outcomes and rates of adverse events including cytokine release syndrome (CRS). V. Investigate chronic lymphocytic leukemia (CLL) persistence post treatment. OUTLINE: Patients receive zanubrutinib orally (PO) twice daily (BID) for up to day 90 and undergo leukaphereis at least 14 days after starting zanubrutinib. Patients receive fludarabine intravenously (IV) and cyclophosphamide IV on days -5 to -3 and liso-cel IV over 5-30 minutes on day 0. Patients also undergo bone marrow (BM) biopsy and lymph node biopsy at screening and follow up, and undergo collection of blood samples and computed tomography (CT), positron emission tomography (PET)/CT, and/or magnetic resonance imaging (MRI) throughout the trial. After study completion, patients are followed for 24 months, and then every 6 months until disease progression or death.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
24
Undergo collection of blood samples
Undergo BM biopsy
Undergo CT and/or PET/CT
Given IV
Given IV
Given IV
Given IV
Undergo lymph node biopsy
Undergo PET/CT
Given PO
Icahn School of Medicine at Mount Sinai
New York, New York, United States
RECRUITINGOhio State University Comprehensive Cancer Center
Columbus, Ohio, United States
RECRUITINGHuntsman Cancer Institute
Salt Lake City, Utah, United States
RECRUITINGOverall response rate
Overall response rate (ORR) will be defined as the proportion of patients achieving a complete or partial response divided by the number of efficacy-evaluable patients according to the Revised Response Criteria for Malignant Lymphoma. Response will be assessed using Lugano criteria 2014. ORR will be reported with two-sided 95% and 80% binomial exact confidence intervals.
Time frame: At 90 days after lisocabtagene maraleucel (liso-cel) infusion
Incidence of adverse events
Adverse event data will be collected on all patients who receive at least one dose of study drug(s). Non-hematologic adverse events (AEs) will be graded according to Common Terminology Criteria for Adverse Events version 5.0. Hematologic AEs will be graded according to chronic lymphocytic leukemia-specific criteria described in the International Workshop on Chronic Lymphocytic Leukemia 2018 guidelines.
Time frame: Up to 2 years
Progression free survival
Will be estimated using Kaplan-Meier methodology. Median estimates and estimates at clinically meaningful time points will be reported with 95% confidence intervals.
Time frame: Time from liso-cel infusion until documented disease progression, or death from any cause, whichever occurs first, assessed up to 2 years
Overall survival
Will be estimated using Kaplan-Meier methodology. Median estimates and estimates at clinically meaningful time points will be reported with 95% confidence intervals.
Time frame: Time from liso-cel infusion until death from any cause, assessed up to 2 years
Duration of response
Will be estimated using Kaplan-Meier methodology. Median estimates and estimates at clinically meaningful time points will be reported with 95% confidence intervals.
Time frame: Time from the first tumor assessment that supports response to the time of confirmed disease progression or death due to any cause, whichever occurs first, assessed up to 2 years
Time to next treatment (TTNT)
Will be estimated using Kaplan-Meier methodology. TTNT will be estimated using the cumulative incidence competing risk method. Median TTNT and TTNT at clinically meaningful time points will be estimated and reported with 95% cumulative incidences.
Time frame: Time from liso-cel infusion until next treatment is initiated, assessed up to 2 years
The Ohio State University Comprehensive Cancer Center
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