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Recurrent Transformed Chronic Lymphocytic LeukemiaPhase 1NCT06735664

Zanubrutinib in Combination With Odronextamab for the Treatment of Patients With Richter's Transformation

A Phase 1 study testing Biopsy, Biospecimen Collection and Bone Marrow Biopsy in people with Recurrent Transformed Chronic Lymphocytic Leukemia and Refractory Transformed Chronic Lymphocytic Leukemia, run by City of Hope Medical Center at 1 site 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
Search all trials

Trial summary

This phase I trial tests the safety and side effects of zanubrutinib in combination with odronextamab and how well it works in treating patients with Richter's transformation. Zanubrutinib, a tyrosine kinase inhibitor, blocks a protein called Bruton tyrosine kinase (BTK), which may help keep cancer cells from growing. Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
Biopsy, Biospecimen Collection and Bone Marrow Biopsy
Could I receive a placebo?
No, everyone receives an active treatment
How many people
23 participants
Where
1 siteUnited States
Study dates
14 Aug 2025to 13 Dec 2027
Phase
Phase 1
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

  • Documented informed consent of the participant and/or legally authorized representative
  • Assent, when appropriate, will be obtained per institutional guidelines
  • Age: ≥ 18 years
  • Eastern Cooperative Oncology Group (ECOG) ≤ 2
  • Histologically confirmed diagnosis of Richter transformation (RT; transformed CLL). Only patients who have diffuse large B-cell lymphoma histology in transformation are eligible (for example, patients with transformation into Hodgkin lymphoma subtype are not eligible)
  • Evidence of CD20 positivity at screening (by immunohistochemistry [IHC] or flow cytometry)
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  • Treatment naïve or relapsed/ refractory disease. Patients with either previously untreated RT and previously treated RT are eligible, regardless of whether or not they had received CLL-directed therapy
  • Radiographically measurable lymphadenopathy (≥ 1.5 cm) or splenomegaly, or bone marrow involvement by diffuse large B cell lymphoma (DLBCL)/RT
  • Fully recovered from the acute toxic effects (except alopecia) to ≤ grade 1 to prior anti-cancer therapy
  • Without bone marrow involvement: Absolute neutrophil count (ANC) ≥ 1,000/mm^3
  • NOTE: A participant may not have received granulocyte colony stimulating factor (G-CSF) within 3 days of first dose of the assigned study treatment in order to meet this eligibility requirement
  • With bone marrow involvement: ANC ≥ 500/mm^3
  • NOTE: A participant may not have received granulocyte colony stimulating factor (G-CSF) within 3 days of first dose of the assigned study treatment in order to meet this eligibility requirement
  • Without bone marrow involvement: Platelets ≥ 50,000/mm^3
  • NOTE: A participant may not have received platelet transfusion within 7 days of first dose of the assigned study treatment in order to meet this eligibility requirements
  • With bone marrow involvement: Platelets ≥ 25,000/mm^3
  • NOTE: A participant may not have received platelet transfusion within 7 days of first dose of the assigned study treatment in order to meet this eligibility requirements
  • With bone marrow involvement: Hemoglobin (Hgb) ≥ 7 g/dL
  • Total bilirubin ≤ 2 x upper limit of normal (ULN) or ≤ 3 x ULN for Gilbert's disease or compensated hemolysis directly attributable to CLL
  • Aspartate aminotransferase (AST) ≤ 3 x ULN
  • Alanine aminotransferase (ALT) ≤ 3 x ULN
  • Alkaline phosphatase (ALP) ≤ 2.5 x ULN or ≤ 5 x ULN if attributed to lymphoma involvement of the liver
  • Serum creatinine ≤ 1.5 x ULN OR creatinine clearance of ≥ 50 mL/min per 24 hour urine test or the Cockcroft-Gault formula
  • If not receiving anticoagulants: International normalized ratio (INR) OR prothrombin (PT) ≤ 1.5 x ULN
  • If on anticoagulant therapy: PT must be within therapeutic range of intended use of anticoagulants
  • If not receiving anticoagulants: Activated partial thromboplastin time (aPTT) ≤ 1.5 x ULN
  • If on anticoagulant therapy: aPTT must be within therapeutic range of intended use of anticoagulants
  • Left ventricular ejection fraction (LVEF) ≥ 45%
  • Note: To be performed within 28 days prior to day 1 of protocol therapy
  • Seronegative for hepatitis C virus (HCV), hepatitis B virus (HBV) (surface antigen negative) and no history of HIV OR
  • If seropositive for HBV or HCV, nucleic acid quantitation must be performed. Viral load must be undetectable
  • HIV-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial
  • Women of childbearing potential (WOCBP): Negative serum pregnancy test
  • Agreement by females and males of childbearing potential to use an effective method of birth control or abstain from heterosexual activity for the course of the study through at least 6 months after the last dose of study therapy. Sperm donation is prohibited during the study and for 6 months after the last dose of the assigned study treatment. Highly effective contraceptive measures include:
  • Stable use of combined (estrogen and progestogen containing) hormonal contraception (oral, intravaginal, transdermal) or progestogen-only hormonal contraception (oral, injectable, implantable) associated with inhibition of ovulation initiated ≥ 2 menstrual cycles prior to screening
  • Intrauterine device (IUD); intrauterine hormone-releasing system (IUS)
  • Bilateral tubal ligation/occlusion
  • Vasectomized partner (provided that the male vasectomized partner is the sole sexual partner of the study patient and that the partner has obtained medical assessment of surgical success for the procedure)
  • Sexual abstinence, only if defined as refraining from heterosexual intercourse during the entire period of risk associated with the study drugs
  • Childbearing potential defined as not being surgically sterilized (men and women) or have not been free from menses for > 1 year (women only)
  • A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a postmenopausal state in women not using hormonal contraception or hormonal replacement therapy. However, in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient to determine the occurrence of a postmenopausal state. The above definitions are according to the clinical trial facilitation group guidance. Pregnancy testing and contraception are not required

Who cannot join

  • Allogeneic bone marrow or organ transplant within 6 months or evidence of active graft versus host diseae (GVHD)
  • Prior CD20-targeted bispecific antibody therapy
  • Chronic systemic corticosteroid use > 10 mg/day of prednisone or equivalent within 72 hours (h) of start of study treatment. Patients who received corticosteroid treatment with ≤ 10 mg/day of prednisone or equivalent must be documented to be on a stable dose of at least 4 weeks' duration prior to day 1 of cycle 1. Patients may have received a brief (≤ 10 days) course of systemic steroids (≤ 80 mg prednisone equivalent per day) up to 24 hours prior to initiation of study therapy for control of lymphoma-related symptoms
  • Therapeutic anticancer antibodies within 2 weeks prior to day 1 of protocol therapy
  • Radio- or toxin-immunoconjugates within 10 weeks prior to day 1 of protocol therapy
  • Live vaccine within 28 days prior to day 1 of protocol therapy
Show all 41Show fewer
  • Any investigational therapy within 28 days or 5 half-lives of the drug, whichever is shorter, prior to the start of study treatment
  • Standard radiotherapy within 14 days of first administration of study treatment
  • Prior organ transplantation
  • Chemotherapy, within 2 weeks prior to day 1 of protocol therapy; targeted therapy within 6 half-lives or two weeks, whichever is shorter
  • Requires treatment with a strong CYP3A4 inducers/ inhibitor while on protocol therapy
  • Uncontrolled immune hemolysis or thrombocytopenia
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to study drug
  • Known hypersensitivity to both allopurinol and rasburicase
  • Unstable cardiac disease as defined by one of the following:
  • Cardiac events such as myocardial infarction (MI) within the past 6 months
  • NYHA (New York Heart Association) heart failure class III-IV
  • Uncontrolled atrial fibrillation or hypertension
  • Arterial or venous thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks), deep vein thrombosis or pulmonary embolism within 3 months before the start of study treatment
  • Unstable angina (angina symptoms at rest), new-onset angina (begun within the last 3 months)
  • Active uncontrolled cardiac arrythmia
  • History or concurrent condition of interstitial lung disease and/or severely impaired lung function
  • Evidence of central nervous system (CNS) involvement within 6 months prior to initiation of study therapy
  • Major surgery (under general anesthesia) within 30 days prior to day 1 of protocol therapy
  • Clinically significant uncontrolled illness
  • Evidence of any active infection (bacterial, viral, fungal, mycobacterial, parasitic or other) at study enrollment or within 2 weeks of study enrollment, if requiring ongoing treatment and/or has the potential to cause disseminated disease or severe infection upon immunosuppression. There should be evidence that the infection has cleared or is well controlled by start of study therapy
  • Active COVID-19 infection
  • Uncontrolled infection with human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV)
  • NOTE: Participants with HIV who have controlled infection (undetectable viral load and CD4 count above 350 cells/uL either spontaneously or on a stable antiviral regimen) are permitted
  • NOTE: Participants who are hepatitis B surface antigen positive or who are hepatitis B core antibody positive should undergo evaluation by a specialist and be considered to have controlled infection (serum hepatitis B virus deoxyribonucleic acid [DNA] polymerase chain reaction [PCR] that is below the limit of detection AND receiving anti-viral therapy for hepatitis B) before they are permitted onto study
  • NOTE: Participants who are HCV antibody positive who have controlled infection (undetectable HCV ribonucleic acid [RNA] by PCR either spontaneously or in response to a successful prior course of anti-HCV therapy) are permitted
  • Cytomegalovirus (CMV) infection as noted by detectable levels on peripheral blood polymerase chain reaction (PCR) assay. Patients who show detectable levels of CMV at screening will need to be treated with appropriate antiviral therapy and demonstrate at least 2 undetectable levels of CMV by PCR assay (at least 7 days apart) before being re-considered for eligibility
  • Other active malignancy. Patients with a prior (in the past 5 years) or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial. History of the following is allowed:
  • Malignancy treated with curative intent and no known active disease present for ≥ 2 years prior to initiation of therapy on current study
  • Adequately treated non-melanoma skin cancer or lentigo maligna (melanoma in situ) without evidence of disease
  • Adequately treated in situ carcinomas (e.g., cervical, esophageal, etc.) without evidence of disease
  • Asymptomatic prostate cancer managed with "watch and wait" strategy
  • Females only: Pregnant or breastfeeding
  • Inability to swallow and retain oral medication
  • Any other condition that would, in the investigator's judgment, contraindicate the patient's participation in the clinical study due to safety concerns with clinical study procedures
  • Prospective participants who, in the opinion of the investigator, may not be able to comply with all study procedures (including compliance issues related to feasibility/logistics)

Trial locations and contacts

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

United States1 site, 1 recruiting

  • City of Hope Medical Center

    Duarte, California, 91010

    Alexey V. Danilov, 626-218-2405, adanilov@coh.org

    Alexey V. Danilov

    Recruiting

Other trials in United States

About this study

Official title: A Phase I Study of Covalent BTK Inhibitor Zanubrutinib in Combination With a CD3-CD20 Bispecific Antibody Odronextamab in Patients With Richter's Transformation

This phase I trial tests the safety and side effects of zanubrutinib in combination with odronextamab and how well it works in treating patients with Richter's transformation. Zanubrutinib, a tyrosine kinase inhibitor, blocks a protein called Bruton tyrosine kinase (BTK), which may help keep cancer cells from growing. Odronextamab is a bispecific monoclonal antibody that can bind to two different antigens at the same time. Odronextamab binds to CD20 found on B-cells (a type of white blood cell) and on many B-cell cancers and to CD3 on T-cells (also a type of white blood cell) and may interfere with the ability of cancer cells to grow and spread. Giving zanubrutinib in combination with odronextamab may be safe, tolerable and/or effective in treating patients with Richter's transformation.

Read the detailed description

PRIMARY OBJECTIVE:

  1. To evaluate safety and tolerability of zanubrutinib administered in combination with odronextamab in patients with Richter's transformation (RT).

SECONDARY OBJECTIVE:

  1. To evaluate efficacy of zanubrutinib administered in combination with odronextamab, based on overall response rate (ORR), complete response (CR) rate, duration of response (DOR), progression-free survival (PFS), and overall survival (OS).

EXPLORATORY OBJECTIVE:

  1. To characterize the T-cell population balance in patients treated with zanubrutinib and odronextamab.

OUTLINE:

Patients receive odronextamab intravenously (IV) over 4 hours on days 1, 2, 8, 9, 15 and 16 of cycle 1 and over 1-4 hours on days 1, 8 and 15 of cycles 2-4 and then on days 1 and 15 of remaining cycles. Patients with CR at cycle 9 may receive odronextamab on day 1 of remaining cycles. Starting with cycle 2, patients also receive zanubrutinib orally (PO) once daily (QD) or twice daily (BID) of each cycle. Cycles repeat every 21 days for cycles 1-4 in the absence of disease progression or unacceptable toxicity then repeat every 28 days for up to cycle 12. After 12 cycles, patients may continue zanubrutinib at investigator's discretion. Patients also undergo echocardiography (ECHO) or multigated acquisition scan (MUGA) and optional bone marrow biopsy at screening and ultrasound guided biopsy of lymph node at screening and during days 2-12 of cycle 2. Additionally, patients undergo blood sample collection and positron emission tomography (PET), or computed tomography (CT) throughout the study.

After completion of study treatment, patients are followed up at 4 and 12 weeks then every 6 months for up to 3 years.

Being tested
Biopsy, Biospecimen Collection, Bone Marrow Biopsy, Computed Tomography, Echocardiography

What participants receive

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

  • BiopsyProcedure or surgery

    Also called BIOPSY_TYPE, Bx

    Undergo ultrasound guided biopsy

  • Biospecimen CollectionProcedure or surgery

    Also called Biological Sample Collection, Biospecimen Collected, Specimen Collection

    Undergo blood sample collection

  • Bone Marrow BiopsyProcedure or surgery

    Also called Biopsy of Bone Marrow, Biopsy, Bone Marrow

    Undergo optional bone marrow biopsy

  • Computed TomographyProcedure or surgery

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

    Undergo CT

  • EchocardiographyProcedure or surgery

    Also called EC

    Undergo ECHO

  • Multigated Acquisition ScanProcedure or surgery

    Also called Blood Pool Scan, Equilibrium Radionuclide Angiography, Gated Blood Pool Imaging, Gated Heart Pool Scan

    Undergo MUGA

  • OdronextamabBiological

    Also called Anti-CD20 x Anti-CD3 Bispecific Monoclonal Antibody REGN1979, REGN1979, WHO 11035

    Given IV

  • Positron Emission TomographyProcedure or surgery

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

    Undergo PET

  • Ultrasound ImagingProcedure or surgery

    Also called 2-Dimensional Grayscale Ultrasound Imaging, 2-Dimensional Ultrasound Imaging, 2D-US, Ultrasonography

    Undergo ultrasound guided biopsy

  • ZanubrutinibDrug

    Also called BGB 3111, BGB-3111, BGB3111, Brukinsa

    Given PO

Study groups in NCT06735664
Study groupRoleWhat they receive
Treatment (odronextamab, zanubrutinib)ExperimentalPatients receive odronextamab IV over 4 hours on days 1, 2, 8, 9, 15 and 16 of cycle 1 and over 1-4 hours on days 1, 8 and 15 of cycles 2-4 and then on days 1 and 15 of remaining cycles. Patients with CR at cycle 9 may receive odronextamab on day 1 of remaining cycles. Starting with cycle 2, patients also receive zanubrutinib PO QD or BID of each cycle. Cycles repeat every 21 days for cycles 1-4 in the absence of disease progression or unacceptable toxicity then repeat every 28 days for up to cycle 12. After 12 cycles, patients may continue zanubrutinib at investigator's discretion. Patients also undergo ECHO or MUGA and optional bone marrow biopsy at screening and ultrasound guided biopsy of lymph node at screening and during days 2-12 of cycle 2. Additionally, patients undergo blood sample collection and PET, or CT throughout the study.
Receives: Procedure: Biopsy; Procedure: Biospecimen Collection; Procedure: Bone Marrow Biopsy; Procedure: Computed Tomography; Procedure: Echocardiography; Procedure: Multigated Acquisition Scan; Biological: Odronextamab; Procedure: Positron Emission Tomography; Procedure: Ultrasound Imaging; Drug: Zanubrutinib

What is being measured

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

  1. Dose limiting toxicity (DLT)

    All non-hematologic toxicities will be coded and graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version (v) 5.0. Hematologic toxicities will be assessed per International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 2018. Cytokine release syndrome (CRS)/immune effector cell associated neurotoxicity syndrome (ICANS) will be coded by American Society for Transplantation and Cellular Therapy (ASTCT) grading for CRS/ICANS. DLTs will be summarized by type, severity, and attribution. DLTs will be individually described.

    Measured: During the first 2 cycles of protocol therapy (cycle length = 21 days)

  2. Incidence of adverse events (AEs)

    All non-hematologic toxicities will be coded and graded according to the NCI CTCAE v 5.0. Hematologic toxicities will be assessed per IWCLL 2018. CRS/ICANS will be coded by ASTCT grading for CRS/ICANS. AEs will be summarized by type, severity, and attribution.

    Measured: Up to 28 days after last dose of study treatment

Secondary outcomes (5)

  1. Overall response rate (ORR)

    ORR will be defined as the proportion of response evaluable patients who achieve a best response of complete response (CR) or partial response (PR) according to Lugano 2014 guidelines on study before any documented disease progression or any subsequent non-Hodgkin lymphoma (NHL) treatment. ORR will be estimated by the binary proportion, along with the 95% exact binomial confidence intervals (CIs).

    Measured: Up to 3 years

  2. CR rate

    Will be defined as the proportion of response evaluable patients who achieve a best response of complete response according to Lugano 2014 guidelines on study before any documented disease progression or any subsequent NHL treatment. CR rate will be estimated by the binary proportion, along with the 95% exact binomial CIs.

    Measured: Up to 3 years

  3. Duration of response (DOR)

    Will be estimated using the product-limit method of Kaplan and Meier along with the Greenwood estimator of standard error; 95% CI will be constructed based on log-log transformation. Median DOR will be estimated when available.

    Measured: From the first achievement of CR or PR to disease progression/relapse or death due to any cause, whichever is earlier, assessed up to 3 years

  4. Progression-free survival (PFS)

    Will be estimated using the product-limit method of Kaplan and Meier along with the Greenwood estimator of standard error; 95% CI will be constructed based on log-log transformation. Median PFS will be estimated when available.

    Measured: From start of protocol treatment to disease relapse/progression or death due to any cause, whichever is earlier, assessed up to 3 years

  5. Overall survival (OS)

    Will be estimated using the product-limit method of Kaplan and Meier along with the Greenwood estimator of standard error; 95% CI will be constructed based on log-log transformation. Median OS will be estimated when available.

    Measured: From start of protocol treatment to death due to any cause, assessed up to 3 years

Timeline

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

  1. First posted16 Dec 2024
  2. Study start14 Aug 2025
  3. Primary completion13 Dec 2027 (estimated)
  4. Study completion13 Dec 2027 (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 1
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
23 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT06735664
Sponsor's protocol ID
23667
Other IDs
NCI-2024-10074, 23667, P30CA033572
Status last verified
Sep 2026
First submitted
11 Dec 2024
Last updated
16 Sep 2026
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing Biopsy, Biospecimen Collection and Bone Marrow Biopsy in people with Recurrent Transformed Chronic Lymphocytic Leukemia and Refractory Transformed Chronic Lymphocytic Leukemia, run by City of Hope Medical Center at 1 site 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 41 inclusion and 41 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 16 Sep 2026. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site 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 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

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?

Each site lists its own contact: choose the nearest one under Trial locations. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Dose limiting toxicity (DLT) (time frame: During the first 2 cycles of protocol therapy (cycle length = 21 days)). The study lists 2 primary outcomes in all. 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 NCT06735664.

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 16 Sep 2026.

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