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This study evaluates a personalized treatment strategy for patients with large B-cell lymphoma (LBCL) whose disease has relapsed or not responded after CD19 CAR-T cell therapy. Researchers believe that the area surrounding the tumor, called the lymphoma microenvironment (LME), plays a major role in why treatments fail.
In this study, researchers will classify patients into four different LME subtypes (GC, IN, ME, or DE) using a standard lab test on their tumor samples. Patients will then be randomly assigned to one of two groups. The control group will receive a standard single-drug therapy (glofitamab). The experimental group will receive a tailored combination therapy based specifically on their tumor's LME subtype. The main hypothesis of this study is that customizing the treatment based on the tumor's microenvironment will significantly improve how long patients live without their disease getting worse (progression-free survival) compared to the standard single-drug approach.
Chimeric antigen receptor T-cell (CAR-T) therapy targeting CD19 has significantly improved outcomes for patients with relapsed or refractory large B-cell lymphoma (R/R LBCL). However, a substantial number of patients still experience treatment failure, and their prognosis is historically very poor, with limited standard treatment options available. Recent scientific evidence suggests that the tumor microenvironment-a complex ecosystem of immune cells, structural cells, and signals surrounding the lymphoma-acts as a critical barrier that drives resistance to CAR-T and other immunotherapies.
This prospective, open-label, randomized clinical trial introduces a "microenvironment-guided" precision immunotherapy approach. Researchers utilize a practical immunohistochemistry (IHC)-based classification system to categorize the lymphoma microenvironment (LME) of each patient into four distinct subtypes: Germinal Center-like (GC), Interstitial (IN), Mesenchymal (ME), and Depleted (DE). Each subtype corresponds to a specific immune suppression mechanism or survival pathway.
Participants will be randomly assigned in a 1:1 ratio to either an experimental group or a control group.
Control Group: Participants will receive monotherapy with glofitamab, a CD3xCD20 bispecific antibody.
Experimental Group: Participants will receive a tailored combination regimen built upon a glofitamab backbone. The additional therapies are specifically matched to their LME subtype to overcome their unique resistance mechanisms. The regimens include:
GC Type: Glofitamab + a BCL-2 inhibitor IN Type: Glofitamab + a PD-1 inhibitor + Lenalidomide ME Type: Glofitamab + local radiotherapy + a BTK inhibitor DE Type: Glofitamab + Chidamide (an HDAC inhibitor) By systematically matching therapies to the specific vulnerabilities of the patient's tumor microenvironment, this study aims to break CAR-T resistance, achieve deeper remissions, and establish a new biomarker-driven treatment paradigm for this challenging clinical scenario.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Experimental: LME-Guided Combination Therapy | Experimental | Participants receive a tailored combination therapy based on their baseline Lymphoma Microenvironment (LME) subtype identified via immunohistochemistry (IHC). The specific regimens are: GC Type: Glofitamab combined with a BCL-2 inhibitor. IN Type: Glofitamab combined with a PD-1 inhibitor and lenalidomide. ME Type: Glofitamab combined with local radiotherapy and a BTK inhibitor. DE Type: Glofitamab combined with chidamide (an HDAC inhibitor). |
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| Active Comparator: Glofitamab Monotherapy | Active Comparator | All participants in this control arm receive single-agent therapy with the CD3xCD20 bispecific antibody glofitamab. The drug will be administered according to the approved product label and standard clinical practice. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| LME-Guided Combination Therapy Regimen | Combination Product | Participants in this arm receive a tailored combination therapy based on their baseline Lymphoma Microenvironment (LME) subtype identified via immunohistochemistry (IHC). The regimens are built on a glofitamab backbone: GC Type: Glofitamab + BCL-2 inhibitor (e.g., Lisaftoclax/Venetoclax) IN Type: Glofitamab + PD-1 inhibitor (e.g., Tislelizumab) + Lenalidomide ME Type: Glofitamab + Local Radiotherapy + BTK inhibitor (e.g., Zanubrutinib) DE Type: Glofitamab + HDAC inhibitor (e.g., Chidamide) |
| Measure | Description | Time Frame |
|---|---|---|
| Progression-Free Survival (PFS) | PFS is defined as the time from the date of randomization to the date of first documented disease progression (PD) or death from any cause, whichever occurs first. Disease response and progression will be assessed by a Blinded Independent Central Review (BICR) according to the Lugano 2014 classification criteria for lymphoma. | From the date of randomization until the first documented disease progression or death from any cause, whichever occurs first, assessed up to approximately 24 months. |
| Measure | Description | Time Frame |
|---|---|---|
| Objective Response Rate (ORR) | ORR is defined as the proportion of participants who achieve a Best Overall Response of Complete Response (CR) or Partial Response (PR). Response will be assessed by a Blinded Independent Central Review (BICR) according to the Lugano 2014 classification criteria for lymphoma. | From the date of randomization until the first documented disease progression or death from any cause, assessed up to approximately 24 months. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Weili Zhao | Contact | +862164370045 | 610707 | zwl_trial@163.com |
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, | Shanghai | Shanghai Municipality | 200020 | China |
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This study uses a parallel-group design with a biomarker-driven experimental arm. Participants are randomly assigned in a 1:1 ratio to either the control arm or the experimental arm. Participants in the control arm receive a single standard therapy (glofitamab monotherapy). Participants in the experimental arm receive one of four distinct combination therapies; the specific combination is determined by their baseline Lymphoma Microenvironment (LME) subtype (GC, IN, ME, or DE), which is identified via immunohistochemistry (IHC) profiling prior to treatment.
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| Glofitamab Monotherapy | Drug | Participants receive glofitamab as a single agent. Administered intravenously. Cycle 1 uses a step-up dosing schedule (e.g., 2.5mg on Day 1, 10mg on Day 8), followed by a target dose (e.g., 30mg) on Day 15 and every 3 weeks thereafter. Pretreatment with obinutuzumab 1000mg is given one week prior to the first dose. |
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| Complete Response Rate (CRR) | CRR is defined as the proportion of participants who achieve a Best Overall Response of Complete Response (CR), as assessed by the BICR according to the Lugano 2014 classification criteria. | From the date of randomization until the first documented disease progression or death from any cause, assessed up to approximately 24 months. |
| Duration of Response (DOR) | DOR is defined as the time from the date of the first documented response (CR or PR) to the date of first documented disease progression (assessed by BICR per Lugano 2014 criteria) or death from any cause, whichever occurs first. | From the date of first documented response (Complete Response or Partial Response) until the first documented disease progression or death from any cause, assessed up to approximately 24 months. |
| Overall Survival (OS) | OS is defined as the time from the date of randomization to the date of death from any cause. | From the date of randomization until the date of death from any cause, assessed up to approximately 24 months. |
| Incidence and Severity of Adverse Events (AEs) | Safety will be evaluated by monitoring the incidence, severity, and causality of adverse events. The severity of general AEs will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0. Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) will be specifically graded using the ASTCT consensus criteria. | From the first dose of study treatment until 90 days after the last dose of study treatment, assessed up to approximately 24 months. |