Recruiting

Phase 1

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

Sponsor:

City of Hope Medical Center

Code:

NCT06735664

Conditions

Recurrent Transformed Chronic Lymphocytic Leukemia

Refractory Transformed Chronic Lymphocytic Leukemia

Richter Syndrome

Transformed Chronic Lymphocytic Leukemia to Diffuse Large B-Cell Lymphoma

Eligibility Criteria

Sex: All

Age: 18+

Healthy Volunteers: Not accepted

Interventions

Biopsy

Biospecimen Collection

Bone Marrow Biopsy

Computed Tomography

Echocardiography

Study Details

Brief 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. 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.

Conditions

Recurrent Transformed Chronic Lymphocytic Leukemia

Refractory Transformed Chronic Lymphocytic Leukemia

Richter Syndrome

Transformed Chronic Lymphocytic Leukemia to Diffuse Large B-Cell Lymphoma

Study ID

NCT06735664

Start date

Aug 14, 2025

Status verified date

Sep, 2025

Completion date

Dec 13, 2027

Anticipated

Primary completion date

Dec 13, 2027

Anticipated

Eligibility Criteria

Sex: All

Age: 18+

Healthy Volunteers: Not accepted

Inclusion Criteria:

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)
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

Exclusion Criteria:

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
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)

Study Design

Enrollment

23 participants

Anticipated

Intervention Model

Single group

Primary purpose

Treatment

Interventions and Outcome Measures

Arms

experimental: Treatment (odronextamab, zanubrutinib)

Patients 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.

Interventions

Biopsy

Undergo ultrasound guided biopsy

Biospecimen Collection

Undergo blood sample collection

Bone Marrow Biopsy

Undergo optional bone marrow biopsy

Computed Tomography

Undergo CT

Echocardiography

Undergo ECHO

Multigated Acquisition Scan

Undergo MUGA

Odronextamab

Given IV

Positron Emission Tomography

Undergo PET

Ultrasound Imaging

Undergo ultrasound guided biopsy

Zanubrutinib

Given PO

Primary outcome measure

Dose limiting toxicity (DLT) [ Time Frame: During the first 2 cycles of protocol therapy (cycle length = 21 days) ]
Incidence of adverse events (AEs) [ Time Frame: Up to 28 days after last dose of study treatment ]

Central Contacts and Locations

Locations

City of Hope Medical Center

Recruiting

Duarte, California, United States, 91010

Contacts

Alexey V. Danilov

626-218-2405 adanilov@coh.org

Principal Investigator:

Alexey V. Danilov

More Information

Sponsor

City of Hope Medical Center

Last update posted

Sep 16, 2025

Last verified

Sep, 2025

Trial information was received from ClinicalTrials.gov and was last updated on 2026-09-09. This information was provided to ClinicalTrials.gov by City of Hope Medical Center on 2025-09-16.