Diffuse Large B-Cell Lymphoma (DLBCL), Mantle Cell Lymphoma (MCL), Primary Mediastinal Large B-cell Lymphoma (PMBCL), Relapsed/Refractory Large B-cell Lymphoma (LBCL), Transforming Follicular Lymphoma (tFL)
Conditions
Brief summary
This study is aimed to explored the safety and efficacy of 7×19-THEMIS CAR-T cell therapy for large B-cell lymphoma and to conduct an exploratory comparison of the 3-month objective response rate (ORR) and complete remission rate (CR rate) between the experimental cohort and the historical control cohort (NCT04833504).
Interventions
BIOLOGICAL7×19-THEMIS CAR-T cells
IL7 and CCL19 Armed anti-CD19 CAR-T with coexpressing Themis
Sponsors
Second Affiliated Hospital, Zhejiang University, School of Medicine
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
1. Voluntarily participate in this study and sign the informed consent form. 2. Age range: 18 - 75 years old. Gender is not restricted. 3. Histologically confirmed large B-cell lymphoma, including: diffuse large B-cell lymphoma (DLBCL), primary mediastinal large B-cell lymphoma (PMBCL), transformed follicular lymphoma (tFL), and mantle cell lymphoma (MCL). 4. CD19-positive (as determined by immunohistochemistry or flow cytometry; based on the most recent tumor biopsy results). 5. Definition of relapsed/refractory: Failure to achieve complete remission (CR) after at least two lines of therapy (which must include a CD20 monoclonal antibody and an anthracycline); or disease progression during any course of treatment; or relapse/progression within 12 months after autologous hematopoietic stem cell transplantation. 6. At least one measurable lesion: any lymph node lesion with a longest dimension \>1.5 cm, or any extranodal lesion with a longest dimension \>1.0 cm, and the lesion shows uptake on PET-CT (SUV greater than the hepatic pool). 7. Absolute neutrophil count in peripheral blood ≥ 1,000/μL; platelet count ≥ 45,000/μL. 8. Cardiac, hepatic, and renal function: creatinine \< 1.5 mg/dL; ALT/AST ≤ 2.5 times the upper limit of normal; total bilirubin \< 1.5 mg/dL; ejection fraction ≥ 50%. 9. Possess sufficient cognitive capacity to voluntarily sign the informed consent form. 10. Participants of reproductive potential must be willing to use effective contraception (from the time of signing the informed consent form until 12 months after CAR-T infusion). 11. The investigator estimates a life expectancy of at least 4 months. 12. Willing to comply with the schedule of visits, dosing regimen, laboratory tests, and other trial procedures.
Exclusion criteria
1. History of other malignant tumors (excluding cured basal cell carcinoma, cervical carcinoma in situ, papillary thyroid carcinoma, etc.). 2. Autologous hematopoietic stem cell transplantation within the past 6 weeks. 3. Any targeted CAR-T therapy within 3 months prior to this CAR-T treatment. 4. Patients who have previously received PD-1 monoclonal antibodies must have a washout period of ≥3 months before enrollment. 5. Received cytotoxic drugs, glucocorticoids (except for prednisone-equivalent doses of ≤10 mg/day), or other targeted therapies within 2 weeks prior to cell collection. 6. Active autoimmune diseases (e.g., systemic lupus erythematosus, inflammatory bowel disease, etc.). 7. Uncontrolled active bacterial, fungal, or viral infections. 8. HIV infection, syphilis; active hepatitis B or C: Hepatitis B: HBsAg-positive and HBV-DNA ≥ 1,000 IU/mL; Hepatitis C: HCV RNA-positive and abnormal liver function. 9. Known central nervous system lymphoma (confirmed by brain MRI or CT and cerebrospinal fluid examination).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Determination of the Recommended Phase II Dose (RP2D) | Up to 3 months | Based on the incidence of DLTs, CAR-T cell kinetics, preliminary efficacy, and safety data from the Phase Ib dose-escalation phase, the Safety Review Committee (SRC) determined the RP2D following a comprehensive evaluation. |
| Objective Response Rate (ORR) | Up to 3 months | At 3 months (±7 days) after infusion, the proportion of patients achieving complete remission (CR) or partial remission (PR) was assessed according to the Lugano 2014 criteria, and a descriptive comparison was made with the historical control cohort. |
| Complete Remission Rate (CR Rate) | Up to 3 months | At 3 months (±7 days) after infusion, the proportion of patients who achieved complete remission (CR) was assessed according to the Lugano 2014 criteria, and a descriptive comparison was made with the historical control cohort. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Incidence and severity of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) graded according to ASTCT 2019 criteria | up to 28 days | The incidence and severity of CRS and ICANS will be assessed according to the American Society for Transplantation and Cellular Therapy (ASTCT) 2019 consensus grading criteria. The incidence of each grade (Grades 1-4) will be summarized, with particular attention to the incidence of Grade ≥3 CRS and Grade ≥3 ICANS. |
| Incidence and duration of Grade ≥3 hematologic toxicities assessed according to CTCAE version 5.0 | up to 28 days | The incidence and duration of Grade ≥3 neutropenia, anemia, and thrombocytopenia will be assessed and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. |
| Incidence of clinically significant infections requiring anti-infective treatment or hospitalization | up to 28 days | The incidence of bacterial, fungal, and viral infections requiring anti-infective treatment or hospitalization will be recorded and summarized. |
| Progression-Free Survival (PFS) | up to 2-5 years | Progression-free survival is defined as the time from CAR-T cell infusion to the first documented disease progression (PD) or death from any cause, whichever occurs first. Median PFS and PFS rates at 12 and 24 months will be estimated using the Kaplan-Meier method. |
| Overall Survival (OS) | up to 2-5 years | Overall survival is defined as the time from CAR-T cell infusion to death from any cause. Median OS and OS rates at 12 and 24 months will be estimated using the Kaplan-Meier method. |
| Duration of Response (DOR) | up to 2-5 years | Among participants who achieve complete response (CR) or partial response (PR), duration of response is defined as the time from the first documented response to disease progression or death from any cause, whichever occurs first. Median DOR will be estimated using the Kaplan-Meier method. |
| In Vivo Kinetics of CAR-T Cells | up to 2-5 years | Measurement of CAR-T Cell Counts in Peripheral Blood and Comparison of Kinetic Parameters |
| Serum Cytokine Dynamics | day-5,day4,day7,day11,day14,day18,day21,day28,month 3 | Measure the concentrations of cytokines such as IL-6, IFN-γ, IL-7, and CCL19 in serum at various time points following infusion. |
| B-Cell Recovery | month1, month3, month6, month9, months12, month24, year3 and year5 | Determine the absolute count of CD19+CD20+ cells in peripheral blood to assess the dynamics of B-cell recovery following infusion. |
Countries
China
Contacts
CONTACTWenbin Qian,Professor
CONTACTWen Lei,Doctor
STUDY_CHAIRWenbin Qian,Professor
Second Affiliated Hospital, Zhejiang University, School of Medicine
Outcome results
None listed