New CAR-T cell therapy for relapsed B-cell non-Hodgkin lymphoma

Autologous TRAC Locus-inserted CD19-targeting Synthetic T-cell Receptor Antigen Receptor T (STAR-T) Cells for Relapsed/Refractory B-cell Non-Hodgkin's Lymphoma

This study is testing a new CAR-T cell therapy for people with relapsed B-cell non-Hodgkin lymphoma to see if it can better target cancer cells while causing fewer side effects.

Quick facts

• Phase: PHASE1; PHASE2
• Study type: Interventional
• Enrollment: 38 (estimated)
• Ages: 18 Years to 75 Years
• Sex: All
• Sponsor: Chinese PLA General Hospital (other)
• Drugs / interventions: chemotherapy, immunotherapy, chimeric antigen receptor, CAR-T
• Locations: 2 sites (Beijing, Beijing and 1 other locations)
• Trial ID: NCT05631912 on ClinicalTrials.gov

What this trial studies

This clinical trial evaluates a novel CAR-T cell therapy called STAR-T, which targets CD19 in patients with relapsed or refractory B-cell non-Hodgkin lymphoma. The therapy involves using CRISPR technology to modify T cells, enhancing their ability to recognize and attack cancer cells while aiming to reduce toxic side effects commonly associated with traditional CAR-T therapies. The study is structured in two phases: a dose escalation phase and an expansion cohort phase, with a total of 19 to 38 patients expected to participate. The primary focus is on assessing the safety and efficacy of this innovative treatment approach.

Who should consider this trial

Good fit: Ideal candidates include adults aged 18-75 with histologically confirmed CD19-positive B-cell non-Hodgkin lymphoma who have relapsed after at least two lines of systemic therapy.

Not a fit: Patients with non-CD19-positive B-cell lymphomas or those who have not received prior systemic therapy may not benefit from this study.

Why it matters

Potential benefit: If successful, this therapy could provide a safer and more effective treatment option for patients with relapsed B-cell non-Hodgkin lymphoma.

How similar studies have performed: Other studies have shown promising results with CAR-T therapies targeting CD19, but this specific approach using STAR-T is novel.

Eligibility criteria

Inclusion Criteria:

1. Age 18-75 (inclusive).
2. Patients with histologically confirmed CD19-positive B-cell NHL, including the following types defined by the World Health Organization (WHO) 2016:

   * Diffuse large B-cell lymphoma not otherwise specified (DLBCL-NOS), including Activated B-cell type (ABC) / Germinal center B-cell Type (GCB);
   * 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.
3. Relapse after treatment with ≥2 lines systemic therapy for all the above disease types, or refractory disease for aggressive types (DLBCL-NOS, PMBCL, TFL and HGBCL). Relapse disease is defined as disease progression after last regimen. Refractory disease is defined as no CR to first-line therapy:

   * PD as best response to first-line therapy, 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.
4. Individuals must have received adequate prior therapy:

   * For MCL, prior therapy must have included:

     * Anthracycline or bendamustine-containing chemotherapy and
     * Anti-CD20 monoclonal antibody (unless investigator determines that tumor is CD20-negative) and
     * Bruton's tyrosine kinase inhibitor (BTKi)
   * For other types, prior therapy must have included:

     * Anti-CD20 monoclonal antibody (unless investigator determines that tumor is CD20-negative) and
     * Anthracycline containing chemotherapy regimen.
   * For individual with transformed FL must have relapse or refractory disease after transformation to DLBCL.
5. The estimated survival time is over 3 months.
6. The Eastern Cooperative Oncology Group (ECOG) score is 0-2.
7. According to Lugano response criteria 2014, there should be at least one evaluable tumor focus. Evaluable tumor focus was defined as that with the longest diameter of intranodal focus \> 1.5cm, the longest diameter of extranodal focus \> 1.0cm assessed by computed tomography (CT) or magnetic resonance imaging (MRI).
8. Subjects must be willing to undergo either excised or large-needle lymph node or tissue biopsy, or provide formalin-fixed paraffin-embedded (FFPE) tumor tissue block or freshly cut unstained slides.
9. Functions of important organs meet the following requirements: Echocardiography showed left ventricular ejection fraction ≥50%. Serum creatinine ≤1.5 × upper limit of normal range (ULN) or endogenous creatinine clearance ≥45mL/min (cockcroft-gault formula); Alanine ULN, Total bilirubin ≤1.5× ULN; Pulmonary function: ≤CTCAE grade 1 dyspnea and oxygen saturation of blood (SaO2) ≥91% in indoor air environment.
10. Blood routine (normal values shall not be obtained with growth factors, and hemocytopenia caused by lymphoma invasion of bone marrow is not subject to conditions below): hemoglobin (Hgb) ≥80g/L, neutrophil count (ANC) ≥1×10\^6/L, platelet (PLT) ≥75×10\^9/L.
11. Pregnancy tests for women of childbearing age shall be negative; Both men and women agreed to use effective contraception during treatment and during the subsequent 1 year.
12. Toxicity from previous antitumor therapy ≤ grade 1 (according to CTCAE version 5.0) or to an acceptable level of inclusion/exclusion criteria (other toxicities such as alopecia and vitiligo considered by the investigator to pose no safety risk to the subject).
13. No obvious hereditary diseases.
14. Able to understand the requirements and matters of the trial, and willing to participate in clinical research as required.
15. Informed consent must be signed.

Exclusion Criteria:

1. During the screening period, there was central nervous system (CNS) invasion or a history of clinically significant central nervous system diseases, such as epilepsy and cerebrovascular diseases.
2. Women who are pregnant or breastfeeding, or who do not agree to use effective contraception during treatment and during the subsequent 1 year.
3. History of allogeneic hematopoietic stem cell transplantation, or organ transplantation.
4. History of other malignancies that have not been in remission.
5. Patients with primary immunodeficiency or autoimmune diseases requiring immunosuppressive therapy.
6. Received radiotherapy within 3 months before enrollment.
7. Received immunotherapy drugs within 4 weeks before enrollment, such as anti-programmed death 1 (PD-1) antibody, anti-programmed death ligand 1 (PD-L1) antibody, CD19/CD3-bispecific antibody, and so on.
8. Patients who received any immunocellular therapy within 6 months before enrollment.
9. Confirmed evidence showing positiveness of anti-CD19 scFv reaction in patient serum.
10. Patients who participated in other clinical trials within 4 weeks prior to enrollment.
11. Uncontrolled infectious diseases or other serious illnesses, including but not limited to infections \[e.g., human immunodeficiency virus (HIV) infection or acute or chronic active hepatitis B (HBV) or C (HCV) infection\], congestive heart failure, unstable angina, arrhythmias, or that pose an unpredictable risk in the opinion of the attending physician.
12. The presence of uncontrollable serous membrane fluid, such as massive pleural effusion or ascites.
13. A history of stroke or intracranial hemorrhage within 3 months prior to enrollment.
14. Major surgery or trauma occurred within 28 days prior to enrollment, or major side effects have not been recovered.
15. History of allergies to any of the ingredients in cell products.
16. Conditions in which a known mental or physical illness interferes with cooperation with the requirements of the study or disrupts the results or interpretation of the results and, in the opinion of the therapeutic investigator, makes the patient unfit for study participation.
17. There is the situation that the researcher's judgment will interfere with the whole study participation; Situations where there is significant risk to the subject; Or interferes with the interpretation of research data.
18. Inability to understand or unwillingness to sign informed consent.
19. Researchers believe that other reasons are not suitable for clinical trials.

Where this trial is running

Beijing, Beijing and 1 other locations

• Biotherapeutic Department, Chinese PLA General Hospital — Beijing, Beijing, China (RECRUITING)
• School of medicine, Tsinghua University & Changping Laboratory — Beijing, Beijing, China (RECRUITING)

Study contacts

• Principal investigator: Weidong Han, Ph.D — Biotherapeutic Department, Chinese PLA General Hospital
• Study coordinator: Weidong Han, Ph.D

Conditions: Non-hodgkin Lymphoma,B Cell