RECRUITING

Zanubrutinib in Combination With Odronextamab for the Treatment of 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

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Study Overview

This clinical trial focuses on testing the efficacy of different digital interventions to promote re-engagement in cancer-related long-term follow-up care for adolescent and young adult (AYA) survivors of childhood cancer.

Description

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.

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

Quick Facts

Study Start:2025-08-14

Study Completion:2027-12-13

Study Type:Not specified

Phase:Not Applicable

Enrollment:Not specified

Status:RECRUITING

Study ID

NCT06735664

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Ages Eligible for Study:18 Years

Sexes Eligible for Study:ALL

Accepts Healthy Volunteers:No

Standard Ages:ADULT, OLDER_ADULT

Inclusion Criteria	Exclusion 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	* 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)

Inclusion Criteria

Exclusion 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

* 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)

Contacts and Locations

Principal Investigator

Alexey V Danilov

PRINCIPAL_INVESTIGATOR

City of Hope Medical Center

Study Locations (Sites)

City of Hope Medical Center

Duarte, California, 91010

United States

Collaborators and Investigators

Sponsor: City of Hope Medical Center

Alexey V Danilov, PRINCIPAL_INVESTIGATOR, City of Hope Medical Center

Study Record Dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Registration Dates

Study Start Date2025-08-14

Study Completion Date2027-12-13

Study Record Updates

Study Start Date2025-08-14

Study Completion Date2027-12-13

Terms related to this study

Additional Relevant MeSH Terms

Recurrent Transformed Chronic Lymphocytic Leukemia
Refractory Transformed Chronic Lymphocytic Leukemia
Richter Syndrome
Transformed Chronic Lymphocytic Leukemia to Diffuse Large B-Cell Lymphoma