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

NCT06735664 | Recruiting Phase 1 DMC FDA Drug

• 3 other identifiers: 23667NCI-2024-10074P30CA033572
• Study Type: interventional
• Target: 23
• Locations: 1 country
• Sites: 1

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

Outcome Measures

Primary Outcomes (2)

• 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.

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

• 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.

  Up to 28 days after last dose of study treatment

Secondary Outcomes (5)

• Overall response rate (ORR)

  Up to 3 years

• CR rate

  Up to 3 years

• Duration of response (DOR)

  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

• Progression-free survival (PFS)

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

• Overall survival (OS)

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

Study Arms (1)

Treatment (odronextamab, zanubrutinib)

EXPERIMENTAL

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.

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

Interventions

Biopsy PROCEDURE

Undergo ultrasound guided biopsy

Also known as: BIOPSY_TYPE, Bx

Treatment (odronextamab, zanubrutinib)

Biospecimen Collection PROCEDURE

Undergo blood sample collection

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

Treatment (odronextamab, zanubrutinib)

Bone Marrow Biopsy PROCEDURE

Undergo optional bone marrow biopsy

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

Treatment (odronextamab, zanubrutinib)

Computed Tomography PROCEDURE

Undergo CT

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

Treatment (odronextamab, zanubrutinib)

Echocardiography PROCEDURE

Undergo ECHO

Also known as: EC

Treatment (odronextamab, zanubrutinib)

Multigated Acquisition Scan PROCEDURE

Undergo MUGA

Also known as: Blood Pool Scan, Equilibrium Radionuclide Angiography, Gated Blood Pool Imaging, Gated Heart Pool Scan, MUGA, MUGA Scan, Multi-Gated Acquisition Scan, Radionuclide Ventriculogram Scan, Radionuclide Ventriculography, RNV Scan, RNVG, SYMA Scanning, Synchronized Multigated Acquisition Scanning

Treatment (odronextamab, zanubrutinib)

Odronextamab BIOLOGICAL

Given IV

Also known as: Anti-CD20 x Anti-CD3 Bispecific Monoclonal Antibody REGN1979, REGN1979, WHO 11035

Treatment (odronextamab, zanubrutinib)

Positron Emission Tomography PROCEDURE

Undergo PET

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 (odronextamab, zanubrutinib)

Ultrasound Imaging PROCEDURE

Undergo ultrasound guided biopsy

Also known as: 2-Dimensional Grayscale Ultrasound Imaging, 2-Dimensional Ultrasound Imaging, 2D-US, Ultrasonography, Ultrasound, Ultrasound Test, Ultrasound, Medical, US

Treatment (odronextamab, zanubrutinib)

Zanubrutinib DRUG

Given PO

Also known as: BGB 3111, BGB-3111, BGB3111, Brukinsa, BTK-InhB

Treatment (odronextamab, zanubrutinib)

Eligibility Criteria

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

You may qualify if:

• 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

You may not qualify if:

• 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:

Sponsors & Collaborators

• City of Hope Medical Center: lead
• National Cancer Institute (NCI): collaborator

Study Sites (1)

City of Hope Medical Center

Duarte, California, 91010, United States

RECRUITING

MeSH Terms

Interventions

Biopsy; Specimen Handling; Magnetic Resonance Spectroscopy; High-Energy Shock Waves; zanubrutinib

Intervention Hierarchy (Ancestors)

Cytodiagnosis; Cytological Techniques; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Diagnostic Techniques, Surgical; Surgical Procedures, Operative; Investigative Techniques; Spectrum Analysis; Chemistry Techniques, Analytical; Ultrasonic Waves; Sound; Radiation, Nonionizing; Radiation; Physical Phenomena

Study Officials

• Alexey V Danilov

  City of Hope Medical Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 11, 2024
• First Posted: December 16, 2024
• Study Start: August 14, 2025
• Primary Completion (Estimated): December 13, 2027
• Study Completion (Estimated): December 13, 2027
• Last Updated: September 16, 2025

Record last verified: 2025-09

Locations

US (1)