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LME-Guided Precision Combination Therapy in B-cell Lymphoma Patients After CD19 CAR-T Failure

2026年5月15日 更新者：Ruijin Hospital

An Exploratory, Two-Arm Study of LME Subtype-Guided Precision Combination Therapy Strategies in Patients With B-Cell Lymphoma After CD19 CAR-T Therapy Failure

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.

研究概览

地位

尚未招聘

条件

干预/治疗

详细说明

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.

研究类型

介入性

注册 (估计的)

60

阶段

  • 阶段2

联系人和位置

本节提供了进行研究的人员的详细联系信息，以及有关进行该研究的地点的信息。

学习联系方式

学习地点

  • 中国
    • Shanghai Municipality
      • Shanghai、Shanghai Municipality、中国、200020
        • Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai,
        • 接触：

参与标准

研究人员寻找符合特定描述的人，称为资格标准。这些标准的一些例子是一个人的一般健康状况或先前的治疗。

资格标准

适合学习的年龄

  • 成人
  • 年长者

接受健康志愿者

不

描述

Inclusion Criteria:

  • Age ≥ 18 years, regardless of gender.
  • Histologically confirmed large B-cell lymphoma (LBCL), including diffuse large B-cell lymphoma (DLBCL, not otherwise specified) or high-grade B-cell lymphoma.
  • Received prior CD19-targeted chimeric antigen receptor (CAR) T-cell therapy.
  • Confirmed stable disease (SD) or progressive disease (PD) at the most recent imaging assessment (according to Lugano 2014 criteria) following CAR-T therapy.
  • Able to provide a formalin-fixed paraffin-embedded (FFPE) tumor tissue sample (fresh biopsy or archival specimen obtained before CAR-T therapy or after recent progression) with sufficient quantity and quality for immunohistochemistry (IHC) testing.
  • Confirmed CD20-positive tumor cells by central laboratory IHC testing.
  • Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1, or 2.
  • Adequate organ function (including bone marrow, liver, kidney, and heart).
  • Women of childbearing potential must agree to use highly effective contraception during the study and for a specified period after the last dose of study drug; male patients must agree to use effective contraception during the study and for a specified period after the last dose.
  • Voluntarily agreed to participate in the study, signed the written informed consent form, and willing to comply with the study visit schedule and other protocol requirements.

Exclusion Criteria:

  • Prior treatment with glofitamab resulting in disease progression.
  • Known severe allergic reactions to any components of the study drugs.
  • Active central nervous system (CNS) lymphoma involvement.
  • Presence of a severe, uncontrolled active infection.
  • Presence of severe cardiovascular or cerebrovascular diseases, uncontrolled diabetes, or uncontrolled hypertension that, in the investigator's judgment, makes the patient unsuitable for study participation.
  • History of or current other malignancies (exceptions: adequately treated basal cell carcinoma of the skin, carcinoma in situ of the cervix, etc.).
  • Pregnant or breastfeeding women.
  • Positive for human immunodeficiency virus (HIV) antibody, or active hepatitis B virus (HBV) infection (HBsAg positive with HBV-DNA > 1x10^3 copies/mL), or active hepatitis C virus (HCV) infection (HCV antibody positive and HCV-RNA positive).
  • Any medical or psychiatric condition that might interfere with study execution or result interpretation, or place the patient at unacceptable risk.
  • Received other anti-tumor therapies (including chemotherapy, radiotherapy, immunotherapy, etc.) within 2 weeks prior to study enrollment, or have not recovered from toxicities of prior therapies to ≤ Grade 1 or baseline levels (excluding alopecia or other irreversible but non-clinically significant toxicities).

学习计划

本节提供研究计划的详细信息，包括研究的设计方式和研究的衡量标准。

研究是如何设计的？

设计细节

  • 主要用途：治疗
  • 分配：随机化
  • 介入模型：并行分配
  • 屏蔽：无（打开标签）

武器和干预

参与者组/臂
干预/治疗
实验性的：Experimental: LME-Guided Combination Therapy

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).
组合产品：LME-Guided Combination Therapy Regimen

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)
有源比较器：Active Comparator: Glofitamab Monotherapy
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.
药品：Glofitamab Monotherapy
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.

研究衡量的是什么？

主要结果指标

结果测量
措施说明
大体时间
Progression-Free Survival (PFS)
大体时间：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.
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.

次要结果测量

结果测量
措施说明
大体时间
Objective Response Rate (ORR)
大体时间：From the date of randomization until the first documented disease progression or death from any cause, assessed up to approximately 24 months.
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.
Complete Response Rate (CRR)
大体时间：From the date of randomization until the first documented disease progression or death from any cause, assessed up to approximately 24 months.
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)
大体时间：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.
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)
大体时间：From the date of randomization until the date of death from any cause, assessed up to approximately 24 months.
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)
大体时间：From the first dose of study treatment until 90 days after the last dose of study treatment, assessed up to approximately 24 months.
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.

合作者和调查者

在这里您可以找到参与这项研究的人员和组织。

赞助

Ruijin Hospital

研究记录日期

这些日期跟踪向 ClinicalTrials.gov 提交研究记录和摘要结果的进度。研究记录和报告的结果由国家医学图书馆 (NLM) 审查，以确保它们在发布到公共网站之前符合特定的质量控制标准。

研究主要日期

学习开始 (估计的)

2026年5月14日

初级完成 (估计的)

2028年5月14日

研究完成 (估计的)

2028年11月1日

研究注册日期

首次提交

2026年5月15日

首先提交符合 QC 标准的

2026年5月15日

首次发布 (实际的)

2026年5月22日

研究记录更新

最后更新发布 (实际的)

2026年5月22日

上次提交的符合 QC 标准的更新

2026年5月15日

最后验证

2026年5月1日

更多信息

与本研究相关的术语

关键字

其他研究编号

  • POST-CART-LME

计划个人参与者数据 (IPD)

计划共享个人参与者数据 (IPD)？

不

药物和器械信息、研究文件

研究美国 FDA 监管的药品

不

研究美国 FDA 监管的设备产品

不

此信息直接从 clinicaltrials.gov 网站检索，没有任何更改。如果您有任何更改、删除或更新研究详细信息的请求，请联系 register@clinicaltrials.gov. clinicaltrials.gov 上实施更改，我们的网站上也会自动更新.

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