Zamtocabtagene autoleucel (MB-CART2019.1) for relapsed or refractory diffuse large B‑cell lymphoma in Japan

A Multi-center Single Arm Phase II Study to Evaluate the Safety and Efficacy of Genetically Engineered Autologous Cells Expressing Anti-CD20 and Anti-CD19 Specific Chimeric Antigen Receptor in Subjects With Relapsed and/or Refractory Diffuse Large B Cell Lymphoma.

This study will test a dual-target CAR T-cell therapy (MB-CART2019.1) that targets CD19 and CD20 in people in Japan whose diffuse large B‑cell lymphoma has returned or not responded after at least two prior therapies.

Quick facts

• Phase: Phase 2
• Study type: Interventional
• Enrollment: 31 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: Miltenyi Biomedicine GmbH (Industry-sponsored)
• Drugs / interventions: rituximab, CAR T, chemotherapy, immunotherapy, Prednisone, cyclophosphamide, fludarabine
• Locations: 5 sites (Tokyo and 4 other locations)
• Trial ID: NCT07288879 on ClinicalTrials.gov

What this trial studies

This is a single-arm, open-label Phase 2 study enrolling patients with relapsed or refractory DLBCL after at least two prior lines of therapy. Participants will have their own T cells collected by leukapheresis, which are engineered to express CARs against CD19 and CD20, and then returned after a short lymphodepleting regimen (cyclophosphamide and fludarabine). The planned infusion dose is 2.5 x 10^6 CAR+ cells per kg given intravenously, with close monitoring for safety, efficacy, and quality of life. Subjects will be followed for up to two years for response, adverse events, pharmacokinetics, and health-related quality of life, with longer-term follow-up under a separate protocol.

Who should consider this trial

Good fit: Ideal candidates are adults in Japan with histologically confirmed DLBCL (or specified related subtypes) whose disease is relapsed or refractory after two or more prior therapies including rituximab and an anthracycline, and who have failed, are ineligible for, or decline autologous stem cell transplant.

Not a fit: Patients whose tumors lack CD19/CD20 expression, who have uncontrolled infections or severe organ dysfunction, or who do not meet the specified eligibility criteria are unlikely to benefit from this therapy.

Why it matters

Potential benefit: If successful, this therapy could produce durable remissions for patients with DLBCL who have exhausted standard treatment options.

How similar studies have performed: Single-target CD19 CAR T therapies have produced remissions in relapsed/refractory DLBCL, and dual-target CD19/CD20 CAR approaches are promising but remain less established and are being explored to reduce antigen-escape relapse.

Eligibility criteria

Inclusion Criteria:

1. Histologically confirmed DLBCL or associated subtype, defined by WHO 2016 classification:

   * DLBCL not otherwise specified (NOS)
   * High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements
   * High-grade B-cell lymphoma, NOS
   * Primary mediastinal (thymic) large B-cell lymphoma
   * Transformed lymphoma (e.g. transformed follicular or marginal zone lymphoma, follicular lymphoma Grade 3B)
2. Relapsed or refractory disease after 2 or more lines of chemotherapy including rituximab and anthracycline and either having failed autologous stem cell transplant (ASCT), or being ineligible for or not consenting to ASCT 2.1 Chemotherapy-refractory disease is defined as one of the following:

   * No response to last line of therapy:

     * Progressive disease (PD) as best response to most recent therapy regimen
     * Stable disease (SD) as best response to most recent therapy with duration no longer than 6 months from last dose of therapy OR
   * Relapsed or persistent disease after prior ASCT for lymphoma

     * Disease progression or relapse less than or equal to 24 months of ASCT
     * If salvage therapy is given post-ASCT, the individual must have had no response to or relapsed after the last line of therapy 2.2 Disease relapse in subjects without prior ASCT is defined as relapse of disease in ≤ 12 months after the last dose of most recent therapy regimen 2.3 Ineligible for ASCT is defined as meeting one of the following criteria:
   * Chemotherapy-refractory disease after salvage therapy
   * Disease progression or relapse ≤ 12 months after salvage therapy
   * Intolerance to salvage therapy

   In addition, all subjects must have:
3. Age ≥18 years
4. Eastern Cooperative Oncology Group (ECOG) performance status that is either 0 or 1 at screening. ECOG performance status of 2 at screen is allowed if the decrease in performance status is due to DLBCL
5. Measurable disease according to Lugano 2014 criteria for assessing fluorodeoxyglucose-positron emission tomography (FDG-PET)/computer tomography (CT) in lymphoma (Cheson et al, 2014)
6. CD19 or CD20 antigen expression on tumor is not required after the most recent chemoimmunotherapy; however, 6.1 Subject must have at least 20 unstained slides of tissue available prior to MB-CART2019.1 infusion 6.2 If archival tissue is not available, subject must be willing to undergo attempted repeat biopsy
7. No clinical suspicion of central nervous system (CNS) lymphoma
8. If the subject has history of CNS disease, then he/she must 8.1. Have no signs or symptoms of CNS disease 8.2. Have no active disease on magnetic resonance imaging (MRI) 8.3. Have no large cell lymphoma present in cerebral spinal fluid (CSF) on cytospin preparation and flow cytometry, regardless of the number of white blood cells (WBCs)
9. If the subject has history of cerebral vascular accident (CVA) 9.1. The CVA event must be greater than 12 months prior to leukapheresis 9.2. Any neurological deficits must be stable
10. An estimated creatinine clearance by Cockcroft-Gault Equation (eGFR) \> 60mL/min
11. Cardiac ejection fraction (EF) ≥ 45% as determined by an echocardiogram (ECHO)
12. Resting O2 saturation \>90% on room air
13. Serum alanine aminotransferase (ALT) / aspartate aminotransferase (AST) \<5 times the Upper Limit of Normal (ULN) for age
14. Total bilirubin \<1.5 mg/dl, except in individuals with Gilbert's syndrome
15. Absolute neutrophil count (ANC) \> 1000/μL
16. Absolute lymphocyte count \> 100/μL
17. Platelet count \> 50,000/μL
18. Estimated life expectancy of more than 3 months other than primary disease
19. Subjects of childbearing or child fathering potential must be willing to practice birth control from the time of enrollment on this study until the follow-up period of the study

Exclusion Criteria:

1. Primary CNS lymphoma
2. Richter's transformed DLBCL arising from chronic lymphocytic leukemia (CLL)
3. Unable to give informed consent
4. Known history of infection with human immunodeficiency virus (HIV) or active hepatitis B (HBsAg positive), unless confirmed to be polymerase chain reaction (PCR) negative; antiviral prophylaxis is required as recommended in the Japanese guidelines for Hepatitis B treatment if HBsAg negative and anti-HBc positive
5. Known history of infection with hepatitis C virus (anti-HCV positive) unless viral load is undetectable per quantitative PCR and/or nucleic acid testing
6. Known history of active seizure or presence of seizure activities or on active anti-seizure medications within the prior 12 months
7. Known history of CVA within prior 12 months
8. Known history or presence of autoimmune CNS disease, such as multiple sclerosis, optic neuritis or other immunologic or inflammatory disease
9. Presence of active CNS disorder that, in the judgment of the investigator, may impair the ability to evaluate neurotoxicity
10. Active systemic fungal, viral or bacterial infection
11. Pregnant or breast-feeding woman
12. Previous or concurrent malignancy with the following exceptions:

    * Adequately treated basal cell or squamous cell carcinoma (adequate wound healing is required prior to study entry)
    * In situ carcinoma of the cervix or breast, treated curatively and without evidence of recurrence for at least 2 years prior to the study
    * Adequately treated breast or prostate carcinoma on hormonal therapies such as Lupron or tamoxifen and in clinical remission of ≥ 2 years
    * A primary malignancy which has been completely resected / treated with curative intent and in complete remission of ≥ 2 years
13. History of non-neurologic autoimmune disease (e.g. Crohn's disease, rheumatoid arthritis, systemic lupus erythematosus) requiring systemic immunosuppressive or systemic disease modifying agents within the last 2 years
14. Medical condition requiring prolonged use of systemic corticosteroids equivalent to Prednisone \>10 mg/day
15. History of myocardial infarction, cardiac angioplasty or stenting, unstable angina, or other clinically significant cardiac disease within 6 months of enrollment
16. Concurrent radiotherapy (allow up to time of leukapheresis)
17. Baseline dementia that would interfere with therapy or monitoring, determined using Immune Effector Cell-Associated Encephalopathy (ICE) Assessment at baseline. (Appendix 6, Section 13.6)
18. History of severe immediate hypersensitivity reaction to any of the agents used in this study
19. Refusal to participate in additional lentiviral gene therapy LTFU protocol
20. Prior CAR T cell therapy for any indication
21. Prior allogeneic stem cell transplant for any indication.
22. Prior bispecific antibodies for cancer therapy
23. Prior T cell receptor-engineered T cell therapy
24. Prior anti CD 19 immunotherapy
25. Hypersensitivity against any drug including MB-CART2019.1 (and the constituents used in the production, ingredients/impurities, including bovine and rodent-derived components), that is scheduled or likely to be given during trial participation, e.g. as part of the mandatory preparative chemotherapy or rescue medication/salvage therapies for treatment related toxicities.

Where this trial is running

Tokyo and 4 other locations

• National Cancer Center Hospital — Tokyo, Japan (Recruiting)
• Toranomon Hospital — Tokyo, Japan (Not_yet_recruiting)
• Juntendo University Hospital — Tokyo, Japan (Not_yet_recruiting)
• Tokyo Metropolitan Komagome Hospital — Tokyo, Japan (Recruiting)
• Keio University Hospital — Tokyo, Japan (Not_yet_recruiting)

Study contacts

• Study coordinator: Clinical Trial Manager

Conditions DLBCL - Diffuse Large B Cell Lymphoma; CAR T Cell Therapy; CAR T Cell therapy; DLBCL