Zanubrutinib and Lisocabtagene Maraleucel for the Treatment of Richter's Syndrome

NCT05873712 | Recruiting Phase 2 DMC FDA Drug

• 2 other identifiers: OSU-22157NCI-2023-03669
• Study Type: interventional
• Target: 24
• Locations: 1 country
• Sites: 3

Brief Summary

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.

Conditions

Transformed Chronic Lymphocytic Leukemia to Diffuse Large B-Cell Lymphoma; Recurrent Transformed Chronic Lymphocytic Leukemia; Refractory Transformed Chronic Lymphocytic Leukemia; Recurrent Transformed B-Cell Non-Hodgkin Lymphoma; Recurrent Transformed Non-Hodgkin Lymphoma; Refractory Transformed Non-Hodgkin Lymphoma; Refractory Transformed B-cell Non-Hodgkin Lymphoma; Refractory Transformed

Keywords

Richter's Transformation; Richter's Syndrome

Outcome Measures

Primary Outcomes (1)

• Overall 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.

  At 90 days after lisocabtagene maraleucel (liso-cel) infusion

Secondary Outcomes (5)

• Incidence of adverse events

  Up to 2 years

• Progression free survival

  Time from liso-cel infusion until documented disease progression, or death from any cause, whichever occurs first, assessed up to 2 years

• Overall survival

  Time from liso-cel infusion until death from any cause, assessed up to 2 years

• Duration of response

  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)

  Time from liso-cel infusion until next treatment is initiated, assessed up to 2 years

Study Arms (1)

Treatment (zanubrutinib, liso-cel)

EXPERIMENTAL

Patients receive zanubrutinib PO BID for up to day 90 and undergo leukaphereis at least 14 days after starting zanubrutinib. Patients receive fludarabine IV and cyclophosphamide IV on days -5 to -3 and liso-cel IV over 5-30 minutes on day 0. Patients also undergo BM biopsy and lymph node biopsy at screening and follow up, and undergo collection of blood samples and CT, PET/CT, and/or MRI throughout the trial.

Procedure: Biospecimen Collection; Procedure: Bone Marrow Biopsy; Procedure: Computed Tomography; Drug: Cyclophosphamide; Drug: Fludarabine; Procedure: Leukapheresis; Biological: Lisocabtagene Maraleucel; Procedure: Lymph Node Biopsy; Procedure: Positron Emission Tomography; Drug: Zanubrutinib

Interventions

Biospecimen Collection PROCEDURE

Undergo collection of blood samples

Also known as: Biological Sample Collection, Biospecimen Collected, Specimen Collection

Treatment (zanubrutinib, liso-cel)

Bone Marrow Biopsy PROCEDURE

Undergo BM biopsy

Also known as: Biopsy of Bone Marrow, Biopsy, Bone Marrow

Treatment (zanubrutinib, liso-cel)

Computed Tomography PROCEDURE

Undergo CT and/or PET/CT

Also known as: CAT, CAT Scan, Computed Axial Tomography, Computerized Axial Tomography, Computerized axial tomography (procedure), Computerized Tomography, CT, CT Scan, tomography

Treatment (zanubrutinib, liso-cel)

Cyclophosphamide DRUG

Given IV

Also known as: (-)-Cyclophosphamide, 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate, Carloxan, Ciclofosfamida, Ciclofosfamide, Cicloxal, Clafen, Claphene, CP monohydrate, CTX, CYCLO-cell, Cycloblastin, Cycloblastine, Cyclophospham, Cyclophosphamid monohydrate, Cyclophosphamide Monohydrate, Cyclophosphamidum, Cyclophosphan, Cyclophosphane, Cyclophosphanum, Cyclostin, Cyclostine, Cytophosphan, Cytophosphane, Cytoxan, Fosfaseron, Genoxal, Genuxal, Ledoxina, Mitoxan, Neosar, Revimmune, Syklofosfamid, WR- 138719

Treatment (zanubrutinib, liso-cel)

Fludarabine DRUG

Given IV

Also known as: Fluradosa

Treatment (zanubrutinib, liso-cel)

Leukapheresis PROCEDURE

Given IV

Also known as: Leukocytopheresis, Therapeutic Leukopheresis

Treatment (zanubrutinib, liso-cel)

Lisocabtagene Maraleucel BIOLOGICAL

Given IV

Also known as: Anti-CD19-CAR Genetically Engineered Autologous T Lymphocytes JCAR017, Anti-CD19-CAR Genetically Engineered Autologous T-lymphocytes JCAR017, Autologous Anti-CD19-EGFRt-4-1BB-zeta-modified CAR CD8+ and CD4+ T-lymphocytes JCAR017, Breyanzi, JCAR 017, JCAR017

Treatment (zanubrutinib, liso-cel)

Lymph Node Biopsy PROCEDURE

Undergo lymph node biopsy

Also known as: Biopsy of Lymph Node

Treatment (zanubrutinib, liso-cel)

Positron Emission Tomography PROCEDURE

Undergo PET/CT

Also known as: Medical Imaging, Positron Emission Tomography, PET, PET Scan, Positron emission tomography (procedure), Positron Emission Tomography Scan, Positron-Emission Tomography, proton magnetic resonance spectroscopic imaging, PT

Treatment (zanubrutinib, liso-cel)

Zanubrutinib DRUG

Given PO

Also known as: BGB-3111, Brukinsa, BTK-InhB

Treatment (zanubrutinib, liso-cel)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Diagnosis of RS - occurrence of diffuse large B-cell lymphoma (DLBCL) in patients with antecedent or concurrent CLL/SLL (CLL/SLL diagnosis per IWCLL 2018 criteria).
• Must have relapsed/refractory disease as defined by one of the following:
• Participants must have undergone \>= 1 prior systemic therapeutic regimen administered for \>= 1 cycle for either CLL or RS, and have had either documented disease progression to the most recent treatment regimen, or refractory disease. OR
• Developed RS while receiving treatment for CLL
• Age \>= 18 years
• Eastern Cooperative Oncology Group (ECOG) performance status =\< 2
• Total bilirubin =\< 2.0 times the institutional upper limit of normal (unless documented Gilbert's syndrome)
• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase \[SGOT\]) =\< 2.5 x institutional upper limit of normal
• Alanine aminotransferase (ALT) (serum glutamic-pyruvic transaminase \[SGPT\]) =\< 2.5 x institutional upper limit of normal
• Creatinine clearance \>= 30 mL/min
• Using 24-hour creatinine clearance or standard Cockcroft-Gault equation
• Absolute lymphocyte count \> 100/uL at screening
• Left ventricular ejection fraction \>= 40% by multigated acquisition (MUGA) or echocardiogram (ECHO)
• Adequate bone marrow independent of growth factor support or infusion support at screening unless evidence shows that the cytopenia(s) is due to marrow involvement by CLL/small lymphocytic lymphoma (SLL). If cytopenias are due to disease in the bone marrow any degree of anemia or thrombocytopenia are allowed, absolute neutrophil count (ANC) must be \>= 500
• Absolute neutrophil count (ANC) \>= 1000/mm\^3 (independent of growth factor support or infusion support at screening unless evidence shows that the cytopenia\[s\] is due to marrow involvement by CLL/SLL). If cytopenias are due to disease in the bone marrow any degree of anemia or thrombocytopenia are allowed, ANC must be \>= 500

You may not qualify if:

• A history of treatment including any of the following: prior CD19 directed therapy, treatment with alemtuzumab within 6 months before enrollment, prior allogeneic hematopoietic stem cell transplant (SCT) or donor lymphocyte infusion (DLI) within 2 months prior to enrollment
• Prior allogeneic stem cell transplant with active graft-versus-host disease (GVHD), or requiring immunosuppressive drugs for treatment of GVHD, or have taken calcineurin inhibitors within 4 weeks prior to consent
• Inadequate recovery from adverse events related to prior therapy to grade =\< 1 (excluding grade 2 alopecia, neuropathy, and hypertension)
• Is unable to swallow oral medication, or has significant gastrointestinal disease that would limit absorption of oral medication
• Active bleeding or history of bleeding diathesis (e.g., hemophilia or von Willebrand disease)
• Uncontrolled autoimmune hemolytic anemia (AIHA) or idiopathic thrombocytopenic purpura (ITP)
• Presence of a gastrointestinal ulcer diagnosed by endoscopy within 3 months before screening
• Clinically significant cardiovascular disease such as symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of screening, or any class 3 or 4 cardiac disease as defined by the New York Heart Association Functional Classification. Note: Subjects with controlled atrial fibrillation/flutter can enroll on study
• Requires or receiving anticoagulation with warfarin or equivalent vitamin K antagonists
• Prothrombin time (PT)/international normalized ratio (INR) or activated partial thromboplastin time (PTT) (in the absence of lupus anticoagulant) \> 2 x upper limit normal (ULN)
• Treatment with a moderate or strong CYP3A inhibitor or inducer within 7 days prior to first dose of zanubrutinib
• Patients may not have an active intercurrent disease or concurrent malignancy that is expected to limit survival to \< 5 years
• Human immunodeficiency virus (HIV) seropositivity at screening
• Subjects with uncontrolled intercurrent illness including, but not limited to ongoing or active infection, unstable angina pectoris, pulmonary abnormalities or psychiatric illness/social situations that would limit compliance with study requirements
• Pregnant or breastfeeding women are excluded from this study because CAR-T cell therapy may be associated with the potential for teratogenic or abortifacient effects. Women of childbearing potential must have a negative serum pregnancy test. Because there is an unknown, but potential risk for adverse events in nursing infants secondary to treatment of the mother with CAR-T cells, breastfeeding should be discontinued. These potential risks may also apply to other agents used in this study

Sponsors & Collaborators

• Aseel Alsouqi: lead
• BeOne Medicines: collaborator

Study Sites (3)

Icahn School of Medicine at Mount Sinai

New York, New York, 10029, United States

RECRUITING

Ohio State University Comprehensive Cancer Center

Columbus, Ohio, 43210, United States

RECRUITING

Huntsman Cancer Institute

Salt Lake City, Utah, 84112, United States

RECRUITING

Related Links

• The Jamesline

MeSH Terms

Interventions

Specimen Handling; Biopsy; Cyclophosphamide; fludarabine; Leukapheresis; Sentinel Lymph Node Biopsy; Magnetic Resonance Spectroscopy; zanubrutinib

Intervention Hierarchy (Ancestors)

Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Investigative Techniques; Cytodiagnosis; Cytological Techniques; Diagnostic Techniques, Surgical; Surgical Procedures, Operative; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds; Cytapheresis; Biological Therapy; Therapeutics; Blood Component Removal; Leukocyte Reduction Procedures; Cell Separation; Lymph Node Excision; Spectrum Analysis; Chemistry Techniques, Analytical

Study Officials

• Jennifer A Woyach, MD

  Ohio State University Comprehensive Cancer Center

  PRINCIPAL INVESTIGATOR

Central Study Contacts

The Ohio State University Comprehensive Cancer Center

CONTACT

800-293-5066; OSUCCCClinicaltrials@osumc.edu

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: May 15, 2023
• First Posted: May 24, 2023
• Study Start: July 28, 2023
• Primary Completion (Estimated): December 31, 2026
• Study Completion (Estimated): December 31, 2026
• Last Updated: March 3, 2026

Record last verified: 2026-02

Data Sharing

• IPD Sharing: Will not share

Locations

US (3)