BCOR and ZC3H12 Genes Knock-out CD19-targeting CAR-T Cell Therapy in r/r B Cell Lymphoma

NCT07009002 | Recruiting Phase 1

• 1 other identifier: CHN-PLAGH-BT-092
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 1

Brief Summary

In this single-center, single-arm, prospective, Phase 1/2 study, the safety and efficacy of autologous BCOR and ZC3H12 genes knock-out CD19-targeting chimeric antigen receptor (CAR) T-cell therapy will be evaluated in patients with refractory/relapsed (r/r) B-cell Lymphoma. For simplicity, we have termed these CD19 CAR T cells lacking ZC3H12A and BCOR as CAR19TIF( immortal-like and functional CD19 CAR T ) cells, reflecting their immortal-like and functional characteristics. In phase 1, 3 eligible patients will be enrolled and receive CAR19TIF cells at a initial dose of 5×10\^5 cells/kg. Based on the results, subsequently an additional 3-15 patients will be enrolled in a "3+3" dose-escalation/decline design to adjust the dose of CAR19TIF cells to achieve optimal safety and efficacy. The recommended Phase 2 dose (RP2D) will then be established. 10 to 12 subjects will be enrolled and receive CAR19TIF cells infusion at dose of RP2D.

Conditions

B Cell Lymphoma

Keywords

CAR-T cells; CD19

Outcome Measures

Primary Outcomes (8)

• Incidence of Adverse Events (AEs)

  AE is defined as any adverse medical event from the date of randomization to 12 months after CAR T cells infusion. Among them, cytokine release syndrome(CRS) and immune cell-associated neurotoxicity syndrome (ICANS) were graded according to American Society for Transplantation and Cellular Therapy (ASTCT) criteria. Other AEs were graded according to common terminology criteria for adverse events (CTCAE) v5.0.

  12 months

• Phase 1: Incidence of Incidence of DLT.

  DLT is defined as any AE related to the investigational drug that occurs within 28 days after administration of the CAR19TIF cells and meets any one of the criteria listed in the DLT criteria: * Grade 3 CRS that does not resolve to grade 2 or lower within 2 weeks; * Grade 3 ICANS lasting for ≥ 7 days; * Any Grade ≥ 4 CRS or ICANS; * Any other Grade ≥ 4 and Grade 3 AEs related to the CAR19TIF cells that lasts for ≥ 14 days, except hematology toxicity.

  First infusion date of CAR-T cells up to 28 days.

• RP2D

  The recommended dose for phase 2 was determined through phase 1 study.

  12 months

• Phase 2: Complete response (CR) rate

  CR is assessed by investigators and based on the Lugano 2014 assessment criterion. CR rate is defined as the proportion of patients who have achieved CR assessed by investigators.

  24 months

• Phase 2: Objective response rate (ORR)

  ORR is defined as the proportion of patients who have achieved CR and partial response (PR) assessed by investigators.

  24 months

• Phase 2: Duration of Response (DOR)

  DOR is defined as the date of their first CR or PR (which is subsequently confirmed) to PD assessed by investigators, or death regardless of cause.

  24 months

• Phase 2: Overall Survival (OS)

  OS is defined as the time from CAR-T cells infusion to the date of death. Subjects who have not died by the analysis data cutoff date will be censored at the last contact date.

  24 months

• Phase 2: Progression Free Survival (PFS)

  PFS is defined as the time from the CAR-T cells infusion date to the date of disease progression assessed by investigators, or death any cause. Participants not meeting the criteria for progression by the analysis data cutoff date were censored at the last evaluable disease assessment date.

  24 months

Secondary Outcomes (7)

• Phase 1 and phase 2: Pharmacokinetics:Level of CAR-positive T cells circulating in blood over time

  12 months

• Phase 1 and phase 2: Pharmacodynamics:Level of CD19+ cells in peripheral blood

  Up to 28 days after infusion.

• Phase 1 and phase 2: Peak level of cytokines in serum (phase 1 and phase 2)

  Up to 28 days after infusion

• Phase 1: 3-month ORR

  3 months

• Phase 1: OS

  24 months

Other Outcomes (2)

• Relationship between infusion dose of CAR T cells and efficacy

  24 months

• To analyze the dynamic changes of CAR T cells after infusion

  24 months

Study Arms (1)

CAR19TIF cells

EXPERIMENTAL

Patients with r/r B Cell Lymphoma conditioning chemotherapy regimen of fludarabine and cyclophosphamide will be administered followed by investigational treatment, CAR19TIF cells.

Biological: CAR19TIF cells; Drug: Fludarabine; Drug: Cyclophosphamide

Interventions

CAR19TIF cells BIOLOGICAL

Phase 1 dose escalation/decline (3+3) : starting dose: 5×10\^5 cells/kg, According to effective expansion and clinical efficacy data, a descending dose escalation model will be adopted: such as 1×10\^5 cells/kg, 5×10\^4 cells/kg. If the 5×10\^5 cells/kg dose group does not achieve efficient expansion and clinical benefit, an ascending dose escalation model will be adopted, such as 2×10\^6 cells/kg, 6×10\^6 cells/kg. Phase 2 : dose of RP2D.

Also known as: BCOR and ZC3H12 genes knock-out CD19 CAR T cells

CAR19TIF cells

Fludarabine DRUG

Intravenous fludarabine 25\~30 mg/m\^2/day on days -5, -4, and -3.

Also known as: Fludarabine Phosphate for Injection

CAR19TIF cells

Cyclophosphamide DRUG

Intravenous cyclophosphamide 250\~500 mg/m\^2/day on days -5, -4, and -3.

Also known as: Cyclophosphamide for Injection

CAR19TIF cells

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age 18-70 (inclusive).
• Subjects who meet the following requirements:
• Histologically confirmed refractory/relapsed B cell Non-Hodgkin's lymphomas (NHL), including the following types defined by World Health Organization (WHO) 2016:
• Diffuse large B-cell lymphoma not otherwise specified (DLBCL NOS);
• Primary mediastinal (thymic) large B-cell lymphoma (PMBCL);
• Transformed follicular lymphoma (TFL);
• High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements (HGBCL);
• Follicular lymphoma (FL);
• Mantle cell lymphoma (MCL) (pathologically confirmed, with documentation of monoclonal B cells that have a chromosome translocation t(11;14)(q13;q32) and/or overexpress cyclin D1);
• Marginal zone lymphoma (MZL), including nodal or splenic marginal zone B-cell lymphoma and mucosa-associated lymphoid tissue (MALT) lymphoma.
• Relapsed disease is defined as disease progression (PD) after achieving disease remission (including CR and PR) with the latest standard regimen.
• Refractory disease is defined as no CR to first-line therapy: Evaluation of PD (never reached response or SD) after standard first-line treatment, or
• SD as best response after at least 4 cycles of first-line therapy (eg,4 cycles of R-CHOP), or
• PR as best response after at least 6 cycles and biopsy-proven residual disease or disease progression ≤ 6 months of therapy, or
• Refractory post-autologous stem cell transplant (ASCT): i. Disease progression or relapsed less than or equal to 12 months of ASCT (must have biopsy proven recurrence in relapsed individuals); ii. If salvage therapy is given post-ASCT, the individual must have had no response to or relapsed after the last line of therapy.

You may not qualify if:

• Expected survival time \< 3 months per Principal Investigator's opinion.
• History of malignancy other than nonmelanoma skin cancer or carcinoma in situ (e.g. cervix, bladder, breast) or follicular lymphoma unless disease free for at least 3 years.
• History of allogeneic hematopoietic stem cell transplantation, or organ transplantation.
• Prior CD19 targeted therapy.
• Patients who have used any of the following agents or treatments within a specific period of time:
• Received any chemotherapy drugs or small molecule targeted drugs within 2 weeks prior to lymphodepletion; 5.2 Received any monoclonal antibodies, antibody drug conjugates (ADCs), or bispecific antibodies within 3 weeks prior to lymphodepletion; 5.3 Received radiotherapy within 6 weeks prior to lymphodepletion. However, if disease progressed at the site of radiotherapy, or if there are positive lesions detected by PET-CT at non-radiotherapy sites, enrollment is allowed.
• Prior CAR-T therapy or other genetically modified T cell therapy.
• Subjects with detectable cerebrospinal fluid malignant cells, or brain metastases, or with a history of central nervous system (CNS) lymphoma or primary CNS lymphoma.
• History of severe, immediate hypersensitivity reaction attributed to lymphodepletion drugs or any component of CAR19TIF cells.
• Presence or suspicion of fungal, bacterial, viral, or other infection that is uncontrolled or requiring intravenous (IV) antimicrobials for management.
• Uncontrolled or active infectious diseases, such as human immunodeficiency virus (HIV) infection, acute or chronic active hepatitis B or C, epstein-barr virus (EBV), and cytomegalovirus (CMV) infection.
• History or presence of CNS disorder such as seizure disorder, cerebrovascular ischemia/hemorrhage, dementia, cerebellar disease, or any autoimmune disease with CNS involvement.
• Subjects with cardiac atrial or cardiac ventricular lymphoma involvement.
• History of myocardial infarction, cardiac angioplasty or stenting, unstable angina, or other clinically significant cardiac disease within 12 months of enrollment.
• Expected or possible requirement for urgent therapy within 6 weeks due to ongoing or impending oncologic emergency (eg, tumor mass effect, tumor lysis syndrome).

Sponsors & Collaborators

• Chinese PLA General Hospital: lead

Study Sites (1)

Biotherapeutic Department of Chinsese PLA Gereral Hospital

Beijing, Beijing Municipality, China

RECRUITING

MeSH Terms

Conditions

Lymphoma, B-Cell

Interventions

fludarabine; fludarabine phosphate; Injections; Cyclophosphamide

Condition Hierarchy (Ancestors)

Lymphoma, Non-Hodgkin; Lymphoma; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Drug Administration Routes; Drug Therapy; Therapeutics; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds

Study Officials

• Weidong Han, Ph.D

  Biotherapeutic Department, Chinese PLA General Hospital

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Weidong Han, Ph.D

CONTACT

010-66937231; hanwdrsw@sina.com

Yang Liu, M.D

CONTACT

010-66939460; liuyang301blood@163.com

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Director of Biotherapeutic Department

Study Record Dates

• First Submitted: May 21, 2025
• First Posted: June 6, 2025
• Study Start: June 20, 2025
• Primary Completion (Estimated): May 31, 2026
• Study Completion (Estimated): May 31, 2027
• Last Updated: June 25, 2025

Record last verified: 2025-06

Locations

CN (1)