Plasma Cell Neoplasms
Conditions
Keywords
in vivo CAR-T Cell Therapy, BCMA, GPRC5D, plasma cell neoplasms
Brief summary
This study aims to assess the safety profile of in vivo BCMA/GPRC5D-targeted CAR-T cell immunotherapy in patients with relapsed or refractory plasma cell neoplasms.
Detailed description
This is a single-center, open-label, single-arm, prospective study designed to evaluate the safety of in vivo BCMA/GPRC5D-targeted CAR-T cell immunotherapy in patients with relapsed or refractory plasma cell neoplasms. The study employs a dose-escalation design to assess safety, tolerability, and preliminary efficacy. Safety assessments primarily focus on potential adverse events (AEs) following infusion of SL4903 injection, including the number of cases, incidence rates, and severity of cytokine release syndrome, immune effector cell therapy-related neurotoxicity, hematologic toxicity, organ toxicity, ect. Efficacy assessments will include overall objective response rate (ORR), event-free survival (EFS), overall survival (OS), progression-free survival (PFS), duration of complete remission, relapse rate, and mortality rate. Exploratory analyses will focus on characterizing the in vivo kinetics of CAR-T cells and the clonal evolution of plasma cell neoplasms during and after consolidation treatment.
Interventions
DRUGIn vivo BCMA/GPRC5D Tandem Dual CAR-T cell
Administration of in vivo BCMA/GPRC5D tandem dual CAR-T cells. Three dose levels (dose A, dose B, dose C) will be evaluated using a standard 3+3 dose-escalation design.
Sponsors
Liping Dou
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
* Voluntary signing of informed consent by the subject or legally authorized representative, with willingness and ability to comply with scheduled visits, study treatment, laboratory tests, and other study procedures. * Diagnosis of relapsed or refractory plasma cell neoplasms meeting the following criteria: 1. Clonal plasma cells confirmed to be BCMA and/or GPRC5D positive by flow cytometry or immunohistochemistry; 2. Previously treated with at least 2 lines of anti-plasma cell neoplasms therapy, with at least 1 complete treatment cycle for each line, and evidence of disease progression within 12 months after the most recent anti-plasma cell neoplasms treatment, or being refractory to both immunomodulatory drugs and proteasome inhibitors, with disease progression within 2 months after the most recent anti-plasma cell neoplasms treatment (according to the IMWG diagnostic criteria) * Age 18 to 75 years (inclusive), male or female. * Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2. * Life expectancy \> 3 months from the date of informed consent. * Hemoglobin (HGB) ≥ 60 g/L (transfusion allowed). * Adequate organ function (hepatic, renal, cardiac, and pulmonary): 1. Creatinine ≤ 2 × ULN; 2. Left ventricular ejection fraction (LVEF) ≥ 50%; 3. Oxygen saturation \> 90%; 4. Total bilirubin ≤ 1.5 × ULN; ALT and AST ≤ 2.5 × ULN. * Willingness to use highly effective contraception from signing of informed consent until 1 year after SL4903 infusion.
Exclusion criteria
* Severe cardiac dysfunction with left ventricular ejection fraction (LVEF) \< 50%. * History of severe pulmonary impairment. * Concurrent diagnosis of another active malignancy. * Uncontrolled active infection. * History of severe autoimmune disease or primary immunodeficiency. * Active hepatitis (defined as HBV DNA or HCV RNA above the lower limit of detection). * Human immunodeficiency virus (HIV) infection or acquired immunodeficiency syndrome (AIDS), or active syphilis. * History of severe hypersensitivity to biological products (including antibiotics). * Allogeneic hematopoietic stem cell transplant recipients with ongoing acute graft-versus-host disease (GVHD) despite discontinuation of immunosuppressive therapy for at least one month prior to screening. * Any other severe comorbidities or laboratory abnormalities that, in the investigator's opinion, would increase the risk to the subject or interfere with study results, rendering the subject unsuitable for participation. * Pregnant or breastfeeding women (including women of childbearing potential who are pregnant or lactating).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number and incidence rate of Each Grade of Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS) | 1 month after treatment | ICANS severity is graded according to the American Society for Transplantation and Cellular Therapy (ASTCT) Consensus Grading, which incorporates the Immune Effector Cell-Associated Encephalopathy (ICE) assessment. The ICE score ranges from 0 to 10, with higher scores indicating better cognitive function. ICANS grade ranges from 1 to 4, where a higher grade indicates a worse outcome. |
| Number and incidence rate of Treatment-Associated Adverse Events (AEs) | 1 years after treatment | All other AEs would be assessed according to the Common Terminology Criteria for Adverse Events (CTCAE, Version 5.0). |
| Number and incidence rate with Each Grade of Cytokine Release Syndrome (CRS) | 1 month after treatment | CRS severity will be graded according to the American Society for Transplantation and Cellular Therapy (ASTCT) Consensus Grading. The grade ranges from 1 to 4, where a higher grade indicates a worse outcome. |
| Dose-limiting toxicities (DLTs) | 1 month after treatment | Dose limiting toxicity will be assessed after injection |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| progression free survival (PFS) | 2 years after treatment | Progression free survival (PFS) refers to the time from treatment to the first disease progression or death of the patient for any reason. |
| duration of response (DOR) | 2 years after treatment | Duration of Response (DOR) refers to the time from the first assessment of plasma cell neoplasms as a complete or partial response to the first assessment of PD (Progressive Disease) or death from any cause. |
| time to progression (TTP) | 2 years after treatment | Time to progression (TTP) refers to the time from treatment to the first plasma cell neoplasms progression. |
| recurrence rate | 2 years after treatment | The recurrence rate refers to the proportion of patients with plasma cell neoplasms recurrence after treatment. |
| Cmax of CAR-T Cells | 1 month after treatment | CAR-T kinetics would be detected by flow cytometry or qPCR in peripheral blood or bone marrow at each important time points. Cmax is the peak expansion value of CAR-T cells. Cmax is the peak expansion value of CAR-T cells. |
| Tmax of CAR-T Cells | 1 month after treatment | CAR-T kinetics would be detected by flow cytometry or qPCR in peripheral blood bone marrow at each important time points. Tmax is the time of the occurrence of expansion peak. |
| AUC(0-28d) | 1 month after treatment | AUC(0-28d) is the area under the peripheral blood CAR-T cell concentration versus time curve calculated from the time of treatment to 28 days post-treatment, using the linear trapezoidal method. |
| Overall Objective Response Rate (ORR) | Day 14, Day 28, Month 2 , Month 3, Month 6, Month 9, Month 12, Month 18, Month24 after the treatment | Overall objective response rate (ORR) refers the sum of the proportions of complete remission (CR) and partial remission (PR). |
| overall survival (OS) | 2 years after treatment | Overall survival (OS) refers to the time from the start of treatment to the death of the patient for any reason. |
Contacts
CONTACTYu ZHAO
PRINCIPAL_INVESTIGATORLiping DOU
Chinese PLA General Hospital
Outcome results
None listed