Odronextamab for Relapsed and Refractory Large B-cell Lymphomas Before CAR-T

Odronextamab for Relapsed/Refractory Large B-Cell Lymphomas Before Definitive Lymphoma-Directed Therapies

This phase II trial tests the effectiveness of odronextamab given before chimeric antigen receptor T (CAR-T) cell therapy (bridging therapy) in patients with large B-cell lymphomas that have come back after a period of improvement (relapsed) or that have not responded to previous treatment (refractory). Odronextamab is a bispecific antibody that can bind to two different antigens at the same time. Odronextamab binds to CD3, a T-cell surface antigen, and CD20 (a tumor-associated antigen that is expressed on B-cells during most stages of B-cell development and is often overexpressed in B-cell cancers) and may interfere with the ability of cancer cells to grow and spread. Bridging therapy has been used to maintain disease control and to increase the chance of successful receipt of CAR-T cell therapy. However, bridging therapy is typically given after leukapheresis, which does not help prevent disease progression between the decision for CAR-T cell therapy and leukapheresis. Giving odronextamab as bridging therapy before leukapheresis may delay disease progression to allow leukapheresis and increase the likelihood of successful CAR-T cell therapy in patients with relapsed or refractory large B-cell lymphomas.

Study Overview

• Status: Recruiting
• Conditions: Recurrent Diffuse Large B-Cell Lymphoma; Refractory Diffuse Large B-Cell Lymphoma; Recurrent Diffuse Large B-Cell Lymphoma, Not Otherwise Specified; Refractory Diffuse Large B-Cell Lymphoma, Not Otherwise Specified; Recurrent High Grade B-Cell Lymphoma; Refractory High Grade B-Cell Lymphoma; Recurrent Grade 3b Follicular Lymphoma; Refractory Grade 3b Follicular Lymphoma; Recurrent Transformed Indolent B-Cell Non-Hodgkin Lymphoma to Diffuse Large B-Cell Lymphoma; Refractory Transformed Indolent B-Cell Non-Hodgkin Lymphoma to Diffuse Large B-Cell Lymphoma; Recurrent Primary Mediastinal Large B-Cell Lymphoma; Refractory Primary Mediastinal Large B-Cell Lymphoma
• Intervention / Treatment: Other: Questionnaire Administration; Procedure: Lumbar Puncture; Procedure: Leukapheresis; Procedure: Computed Tomography; Procedure: Positron Emission Tomography; Procedure: Bone Marrow Aspiration; Procedure: Bone Marrow Biopsy; Biological: Odronextamab; Procedure: Biospecimen Collection; Biological: Chimeric Antigen Receptor T-Cell Therapy; Procedure: Biopsy Procedure

Detailed Description

OUTLINE:

Patients receive odronextamab intravenously (IV) on days 1, 2, 8, 9, 15 and 16 of cycle 1 (dose step-up), and on days 1, 8 and 15 of cycles 2-4 and then once every other week of remaining cycles. Cycles repeat every 21 days for the first 4 cycles, then every other week for up to a total of 12 months (including the first 2 cycles). After 2 cycles, patients undergo leukapheresis followed by lymphodepletion and CAR-T infusion per standard of care. If there is a significant delay of leukapheresis, patients may receive up to 12 additional weeks of treatment. Patients who achieve CR after cycle 2 may opt out of leukapheresis and CAR-T cell infusion and may continue to receive odronextamab in the absence of disease progression or unacceptable toxicity. Patients undergo positron emission tomography (PET)/computed tomography (CT), collection of blood and oral or rectal swab samples and tissue biopsy throughout the study. Additionally, patients may undergo lumbar puncture and bone marrow aspiration and/or biopsy on study.

After completion of study treatment, patients are followed till 90 days or the initiation of the next lymphoma directed therapy for toxicity check, and total duration of follow-up is up to 5 years.

• Study Type: Interventional
• Enrollment (Estimated): 27
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Mengyang Di, MD, PhD; Phone Number: 206-606-2509; Email: mydi@fredhutch.org

Study Locations

• United States
  • Washington
    • Seattle, Washington, United States, 98109
      • Recruiting
      • Fred Hutch/University of Washington Cancer Consortium
      • Contact: Mengyang Di, MD, PhD; Phone Number: 206-606-2509; Email: mydi@fredhutch.org
      • Principal Investigator: Mengyang Di, MD, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Histologically confirmed large B cell lymphoma, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, primary mediastinal large B-cell lymphoma, high grade B-cell lymphoma, DLBCL arising from indolent lymphoma, follicular lymphoma (FL) grade 3B
• Measurable disease, defined as at least one measurable lesion ≥ 15 mm on PET, CT, or magnetic resonance imaging (MRI) within one month of screening, according to the International Working Group consensus response evaluation criteria in lymphoma
• Prior frontline therapy for large B cell lymphoma must have failed the patient, and criteria must be met for receiving commercial axicabtagene ciloleucel (axi-cel), lisocabtagene maraleucel (liso-cel), or tisagenlecleucel (tisa-cel) per Food and Drug Administration (FDA) label
• Age ≥ 18 years
• Capable of understanding and providing a written informed consent
• Prior treatment with an anti-CD20 antibody therapy
• Eastern Cooperative Oncology Group performance status of 0-1; we allow enrollment of patients with a performance status of 2 if it is attributed to lymphoma per discretion of the treating physician or principal investigator (PI)
• Creatinine clearance ≥ 45 mL/min calculated by Cockcroft-Gault equation
• Total bilirubin ≤ 1.5 x the upper limit of normal (ULN), except in patients with Gilbert's syndrome
• Aspartate aminotransferase and alanine aminotransferase ≤ 2.5 x the ULN
• Adequate pulmonary function, defined as ≤ grade 1 dyspnea and oxygen saturation (SpO2) ≥ 92% on room air
• Adequate cardiac function, defined as left ventricular ejection fraction ≥ 50% and without evidence for pericardial effusion
• Platelet count ≥ 75 x 10^9 /L
• Hemoglobin (Hg) level ≥ 9 g/dL
• Absolute neutrophil count (ANC) ≥ 1 x 10^9 /L
• Patients with bone marrow involvement or splenic sequestration: Platelet count ≥ 25 x 10^9 /L
• Patients with bone marrow involvement or splenic sequestration: Hg ≥ 7.0 g/dL
• Patients with bone marrow involvement or splenic sequestration: ANC ≥ 0.5 x 10^9 /L
• Negative serum pregnancy test within 2 days of initiating odronextamab for women of childbearing potential (WOCBP), defined as those who have not been surgically sterilized or who have not been free of menses for at least 1 year
• Fertile male and WOCBP patients must be willing to use highly effective contraceptive methods from study recruitment to at least 6 months after the CAR T-cell infusion
• Patients must not provide egg or sperm donation until at least 6 months after the completion of the last dose of Odron

Exclusion Criteria:

• Detectable cerebrospinal fluid malignant cells, or brain metastases, or with a history of cerebrospinal fluid malignant cells or brain metastases. Patients with a history of secondary central nervous system (CNS) lymphoma may be eligible provided that there has been no evidence of CNS disease from lymphoma for at least 3 months at the time of screening
• History of a seizure disorder, cerebrovascular ischemia/hemorrhage, dementia, cerebellar disease, or any autoimmune disease with central nervous system (CNS) involvement
• Standard anti-neoplastic chemotherapy (non-biologic) within 5-times the half-life or within 2 weeks, whichever is shorter, prior to first administration of study drug
• Standard radiotherapy within 2 weeks of first administration of study drug
• Prior treatment with an anti-CD20 x anti-CD3 bispecific therapy, unless all the following are met: disease responded to prior bispecific therapy (CR or PR per Lugano criteria) and did not experience disease progression within 12 months of the last dose of prior bispecific therapy, and the tumor must still express CD20 (CD20 examination per standard of care [SOC])
• Allogeneic stem cell transplantation
• Any CAR-T cell therapy
• Patients may not be receiving other investigational agents
• Treatment with rituximab, alemtuzumab, or other investigational or commercial biologic agent within 2 weeks prior to first administration of study drug
• Immunosuppressive therapy (other than biologic) within 2 weeks of first administration of study drug
• Treatment with an investigational non-biologic agent within 2 weeks of first administration of study drug
• History of allergic reactions attributed to compounds of similar chemical or biologic composition of study drug
• History of hypersensitivity to any compound in the tetracycline antibiotics group
• Concurrent active malignancy for which the patient is receiving systemic treatment, unless approved by PI
• Known active and uncontrolled bacterial, viral, fungal, mycobacterial, or other infection
• Evidence of significant concurrent disease or medical condition that could interfere with the conduct of the study, or put the patient at significant risk including, but not limited to, significant cardiovascular disease (e.g., New York Heart Association class III or IV cardiac disease, myocardial infarction within the previous 6 months, unstable arrhythmias, or unstable angina) and/or significant pulmonary disease (e.g., obstructive pulmonary disease and history of symptomatic bronchospasm)
• Ongoing systemic corticosteroid treatment, with the exception of corticosteroid use for other (non-tumor and non-immunosuppressive) indications up to a maximum of 10 mg/day of prednisone or equivalent. A short course of corticosteroid for lymphoma disease control during screening is allowed
• Infection with human immunodeficiency virus (unless viral load is undetectable and CD4 count ≥ 400) or chronic infection with hepatitis B virus or hepatitis C virus. Patients with hepatitis B (hepatitis B surface antigen positive [HepBsAg+]) with controlled infection were permitted upon consultation with the physician managing the infection
• Known hypersensitivity to both allopurinol and rasburicase
• Pregnant or breast-feeding women
• Administration of live vaccination within 28 days of first administration of study drug

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Treatment (odronextamab); Patients receive odronextamab IV based on the following schedules: Step-up dosing during cycle 1: 0.2 mg on C1D1, 0.5 mg on C1D2, 2 mg on C1D8 and C1D9, respectively, and 10 mg on C1D15 and C1D16, respectively (0.7/4/20 regimen).; Dosing during cycles 2-4: Odron will be given at 160 mg weekly.; Once every other week at 320 mg of remaining cycles. Please see the Detailed Description for additional information.

Other: Questionnaire Administration; Ancillary studies; Procedure: Lumbar Puncture; Undergo lumbar puncture; Other Names: LP; Spinal Tap; Procedure: Leukapheresis; Undergo leukapheresis; Other Names: Leukocytopheresis; Therapeutic Leukopheresis; Leukocyte Adsorptive Apheresis; White Blood Cell Reduction Apheresis; Procedure: Computed Tomography; Undergo PET/CT; Other Names: CT; CAT; CAT Scan; Computed Axial Tomography; Computerized Axial Tomography; Computerized Tomography; CT Scan; tomography; Computerized axial tomography (procedure); Computerized Tomography (CT) scan; Procedure: Positron Emission Tomography; Undergo PET/CT; Other Names: Medical Imaging, Positron Emission Tomography; PET; PET Scan; Positron Emission Tomography Scan; Positron-Emission Tomography; proton magnetic resonance spectroscopic imaging; PT; Positron emission tomography (procedure); Procedure: Bone Marrow Aspiration; Undergo bone marrow aspiration; Procedure: Bone Marrow Biopsy; Undergo bone marrow biopsy; Other Names: Biopsy of Bone Marrow; Biopsy, Bone Marrow; Biological: Odronextamab; Given IV; Other Names: REGN1979; Anti-CD20 x Anti-CD3 Bispecific Monoclonal Antibody REGN1979; WHO 11035; Procedure: Biospecimen Collection; Undergo collection of blood and oral or rectal swab samples; Other Names: Biological Sample Collection; Biospecimen Collected; Specimen Collection; Biological: Chimeric Antigen Receptor T-Cell Therapy; Undergo CAR-T cell therapy; Other Names: CAR T Infusion; CAR T Therapy; CAR T-cell Therapy; Chimeric Antigen Receptor T-cell Infusion; Procedure: Biopsy Procedure; Undergo tissue biopsy; Other Names: Bx

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Failure to undergo leukapheresis	Will include failures due to disease progression or adverse events (AEs) due to odronextamab (Odron), or requirement of other lymphoma-directed therapy for bridging before leukapheresis due to lack of response. Will report the total number and percentage with 95% confidence interval (CI).	Up to 5 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Receipt of chimeric antigen receptor T-cell therapy (CAR-T)	Will estimate the total number and percentage with 95% CI of patients who receive CAR-T cell infusion. Patients who achieve complete response (CR) after 2 cycles of Odron and opt out of leukapheresis will be excluded from the estimation of the percentage. Will also report the reasons why patients do not eventually receive CAR-T.	Up to 5 years
Overall response rate (ORR) following bridging prior to CAR-T infusion	ORR includes CR, partial response, stable disease. Will report the total number and percentage with 95% CI of patients who achieve response on positron emission tomography/computed tomography (PET/CT) scans before CAR-T cell infusion. Patients who receive CAR-T cell infusion will be included in the estimation of this percentage.	Up to 5 years
Progression free survival (PFS) following CAR-T infusion	Will estimate the median with interquartile range of the progression free duration. Will also report the percentage with 95% CI.	Up to 2 years
CR rate	Will report the total number and percentage with 95% CI of patients who achieve CR on the PET/CT scans following CAR-T cell infusion.	At 1 month after CAR-T
Incidence of AEs	All AEs will be graded in severity according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0. Cytokine release syndrome and immune effector cell associated neurotoxicity syndrome will be graded by the American Society for Transplantation and Cellular Therapy Consensus Grading systems. Will report the rate and grade of each AE, including unsuccessful CAR-T production.	Up to 90 days after the last dose of Odron or the initiation of the next lymphoma directed therapy, whichever occurs first
PFS in patients who achieve CR after 2 cycles of Odron, choose to opt out of CAR-T, and receive up to a total of 12 months of Odron	Will report the median duration of PFS with 95% CI in this group of patients.	Up to 5 years

Collaborators and Investigators

• Sponsor: University of Washington
• Collaborators: Regeneron Pharmaceuticals
• Investigators: Principal Investigator: Mengyang Di, MD, PhD, Fred Hutch/University of Washington Cancer Consortium

Study record dates

Study Major Dates

• Study Start (Actual): September 4, 2025
• Primary Completion (Estimated): April 10, 2028
• Study Completion (Estimated): April 11, 2033

Study Registration Dates

• First Submitted: January 14, 2025
• First Submitted That Met QC Criteria: January 14, 2025
• First Posted (Actual): January 20, 2025

Study Record Updates

• Last Update Posted (Actual): May 6, 2026
• Last Update Submitted That Met QC Criteria: May 4, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms; Immune System Diseases; Neoplasms by Histologic Type; Lymphatic Diseases; Lymphoproliferative Disorders; Immunoproliferative Disorders; Lymphoma, Non-Hodgkin; Lymphoma, B-Cell; Lymphoma; Hemic and Lymphatic Diseases; Lymphoma, Large B-Cell, Diffuse; Investigative Techniques; Therapeutics; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Punctures; Surgical Procedures, Operative; Cytological Techniques; Cytodiagnosis; Diagnostic Techniques, Surgical; Chemistry Techniques, Analytical; Spectrum Analysis; Biological Therapy; Cytapheresis; Blood Component Removal; Leukocyte Reduction Procedures; Cell Separation; Diagnostic Techniques, Neurological; Immunologic Techniques; Immunomodulation; Adoptive Transfer; Immunization, Passive; Immunization; Immunotherapy; Biopsy; Specimen Handling; Magnetic Resonance Spectroscopy; Leukapheresis; Spinal Puncture; Immunotherapy, Adoptive
• Other Study ID Numbers: RG1124641; NCI-2024-10534 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); FHIRB0020747 (Other Identifier: Fred Hutch/University of Washington Cancer Consortium)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No