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Recurrent Transformed Chronic Lymphocytic LeukemiaPhase 2NCT05873712

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

A Phase 2 study testing Biospecimen Collection, Bone Marrow Biopsy and Computed Tomography in people with Recurrent Transformed Chronic Lymphocytic Leukemia and Refractory Transformed Chronic Lymphocytic Leukemia, run by Aseel Alsouqi at 3 sites in United States.

Recruiting

Looking for participants now. Contact the study team or a site below to ask about taking part.

Sites and contacts
Official record
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Trial 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). Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
Biospecimen Collection, Bone Marrow Biopsy and Computed Tomography
Could I receive a placebo?
No, everyone receives an active treatment
How many people
24 participants
Where
3 sitesUnited States
Study dates
28 Jul 2023to 31 Dec 2026
Phase
Phase 2
Are there results?
Not yet: the study is under way

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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
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  • 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
  • Platelets >= 30,000/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
  • Hemoglobin >= 7 g/dL (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
  • Radiographically measurable lymphadenopathy (or measurable extra-nodal disease) per Lugano criteria
  • Must meet all institutional standards for receiving CAR T-cell therapy
  • Subjects (or legal guardians) must have the ability to understand and the willingness to sign a written informed consent document
  • For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use a contraceptive method with a failure rate of < 1% per year, initiated prior to first dose of study drug, during the treatment period and for at least 1 year after the CAR-T cell infusion or 1 month after last dose of zanubrutinib, whichever is longer.
  • A woman is considered to be of childbearing potential if she is postmenarcheal, has not reached a postmenopausal state (< 12 continuous months of amenorrhea with no identified cause other than menopause), and has not undergone surgical sterilization (removal of ovaries and/or uterus). Examples of contraceptive methods with a failure rate of < 1% per year include bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices
  • For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures, and agreement to refrain from donating sperm, as defined below:
  • With female partners of childbearing potential, men must remain abstinent or use a condom plus an additional contraceptive method that together result in a failure rate of < 1% per year during the treatment period and for at least 1 year after the anti-CD19 CAR-T cell infusion or 1 month after last dose of zanubrutinib, whichever is longer. Men should avoid fathering a child and refrain from donating sperm during this same period.
  • With pregnant female partners, men must remain abstinent or use a condom during the treatment period and for at least 1 year after the human anti- CD19 CAR-T cell infusion or 1 month post last dose of zanubrutinib, whichever is longer, to avoid potential embryonal or fetal exposure. The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception

Who cannot join

  • 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)
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  • 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
  • Evidence of myelodysplasia or cytogenetic abnormality indicative of myelodysplasia on any bone marrow biopsy prior to initiation of therapy
  • Serologic status reflecting active hepatitis B or C infection at screening. Patients that are positive for hepatitis B core antibody, hepatitis B surface antigen (HBsAg), or hepatitis C antibody must have a negative polymerase chain reaction (PCR) at screening. PCR positive patients will be excluded
  • History of autoimmune disease (i.e. rheumatoid arthritis, systemic lupus erythematosus) with requirement of immunosuppressive medication within 6 months
  • Chronic use of corticosteroids >= 20mg prednisone equivalent PO daily
  • Live vaccines given in 28 days prior to lymphodepleting chemotherapy

Trial locations and contacts

3 sites in 1 country. Contact the study team or a site near you to ask about taking part.

The Ohio State University Comprehensive Cancer Center contact

800-293-5066

OSUCCCClinicaltrials@osumc.edu

United States3 sites, 3 recruiting

  • Ohio State University Comprehensive Cancer Center

    Columbus, Ohio, 43210

    Jennifer A Woyach, MD, 614-293-8165, Jennifer.Woyach@osumc.edu

    Jennifer A Woyach, MD

    Recruiting

  • Icahn School of Medicine at Mount Sinai

    New York, New York, 10029

    Patricia Worker, (212) 824-7337, patricia.worker@mssm.edu

    Adam Kittai, MD

    Recruiting

  • Huntsman Cancer Institute

    Salt Lake City, Utah, 84112

    Lindsey Gilstrap, 801-213-5652, lindsey.gilstrap@hci.utah.edu

    Rachel Kingsford, 801-585-0115, rachel.kingsford@hci.utah.edu

    Recruiting

Other trials in United States

About this study

Official title: A Phase II Study Evaluating the Safety and Efficacy of the Combination of Zanubrutinib Plus Lisocabtagene Maraleucel for Richter's Syndrome

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.

Read the detailed description

PRIMARY OBJECTIVE:

  1. To evaluate the efficacy of the combination of zanubrutinib and lisocabtagene maraleucel (liso-cel) for the treatment of Richter's syndrome (RS).

SECONDARY OBJECTIVES:

  1. 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:

  1. 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).

  1. 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.

Being tested
Biospecimen Collection, Bone Marrow Biopsy, Computed Tomography, Cyclophosphamide, Fludarabine
Keywords
Richter's Transformation, Richter's Syndrome

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Biospecimen CollectionProcedure or surgery

    Also called Biological Sample Collection, Biospecimen Collected, Specimen Collection

    Undergo collection of blood samples

  • Bone Marrow BiopsyProcedure or surgery

    Also called Biopsy of Bone Marrow, Biopsy, Bone Marrow

    Undergo BM biopsy

  • Computed TomographyProcedure or surgery

    Also called CAT, CAT Scan, Computed Axial Tomography, Computerized Axial Tomography

    Undergo CT and/or PET/CT

  • CyclophosphamideDrug

    Also called (-)-Cyclophosphamide, 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate, Carloxan, Ciclofosfamida

    Given IV

  • FludarabineDrug

    Also called Fluradosa

    Given IV

  • LeukapheresisProcedure or surgery

    Also called Leukocytopheresis, Therapeutic Leukopheresis

    Given IV

  • Lisocabtagene MaraleucelBiological

    Also called 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

    Given IV

  • Lymph Node BiopsyProcedure or surgery

    Also called Biopsy of Lymph Node

    Undergo lymph node biopsy

  • Positron Emission TomographyProcedure or surgery

    Also called Medical Imaging, Positron Emission Tomography, PET, PET Scan, Positron emission tomography (procedure)

    Undergo PET/CT

  • ZanubrutinibDrug

    Also called BGB-3111, Brukinsa, BTK-InhB

    Given PO

Study groups in NCT05873712
Study groupRoleWhat they receive
Treatment (zanubrutinib, liso-cel)ExperimentalPatients 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.
Receives: 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

What is being measured

The primary outcome is the main question the study is designed to answer.

  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.

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

Secondary outcomes (5)

  1. 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.

    Measured: Up to 2 years

  2. 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.

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

  3. 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.

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

  4. 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.

    Measured: 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

  5. 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.

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

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted24 May 2023
  2. Study start28 Jul 2023
  3. Primary completion31 Dec 2026 (estimated)
  4. Study completion31 Dec 2026 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
24 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT05873712
Sponsor's protocol ID
OSU-22157
Other IDs
NCI-2023-03669
Status last verified
Feb 2026
First submitted
15 May 2023
Last updated
3 Mar 2026
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
No

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Biospecimen Collection, Bone Marrow Biopsy and Computed Tomography in people with Recurrent Transformed Chronic Lymphocytic Leukemia and Refractory Transformed Chronic Lymphocytic Leukemia, run by Aseel Alsouqi at 3 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 25 inclusion and 20 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: looking for participants now, as of the sponsor's last update on 3 Mar 2026. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 3 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

This study is still under way. Results are not available in the source record yet.

How can a doctor refer a patient or contact the research team?

Contact The Ohio State University Comprehensive Cancer Center (800-293-5066, OSUCCCClinicaltrials@osumc.edu), or a site near the patient. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Overall response rate (time frame: At 90 days after lisocabtagene maraleucel (liso-cel) infusion). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT05873712.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 3 Mar 2026.

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