Multiple Myeloma
Conditions
Brief summary
This is a single-center, open-label, single-arm study to evaluate the safety and efficacy of bispecific BCMA-GPRC5D Chimeric antigen receptor (CAR) T-cells in patients with relapsed or refractory multiple myeloma who received three or more lines of therapy.
Detailed description
B-cell maturation antigen (BCMA)-targeted Chimeric antigen receptor (CAR) T-cell therapy has yielded satisfactory clinical outcomes in patients with relapsed or refractory (R/R) multiple myeloma (MM). However, BCMA-targeted CAR-T cells cannot achieve a favorable response in patients with dim or negative BCMA expression on the tumor surface at baseline or relapse. G protein-coupled receptor, class C, group 5, member D (GPRC5D) is highly distributed on MM cells and proves to be a promising target for MM. In normal tissues, it is restrictedly expressed in hair follicle, rendering it a safe target for CAR-T cell therapy as well. To construct a bispecific BCMA-GPRC5D CAR structure would help mitigate the antigen escape and elevates the clinical efficacy. This is an investigational study. The objectives are to evaluate the safety and efficacy of BCMA-GPRC5D CAR-T cells in adult patients with relapsed or refractory MM disease.
Interventions
DRUGFludarabine + Cyclophosphamide + BCMA-GPRC5D CAR-T Cells
fludarabine 30 mg/m2 and cyclophosphamide 300 mg/m2 both on three consecutive days during D-7 to D-3 BCMA-GPRC5D CAR-T Cells on day 0
Sponsors
Guangzhou Bio-gene Technology Co., Ltd
Union Hospital, Tongji Medical College, Huazhong University of Science and Technology
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. Patient or his or her legal guardian voluntarily participates in and signs an informed consent form; 2. Aged ≥ 18 years and ≤ 75 years; 3. Diagnosed as Multiple Myeloma (MM) according to the international standard for multiple myeloma (IMWG); 4. The presence of measurable disease at screening meets one of the following criteria:Serum M-protein ≥ 1.0 g/dL or Urine M-protein ≥ 200 mg/24h or diagnosed as Light-chain MM without measurable disease in serum and urine; Serum free light chain ≥ 10 mg/dL with an abnormal κ/λ ratio; 5. Patients must relapse or be refractory after three or more lines of therapy, which at least include: one Proteasome Inhibitor (PI), one Immunomodulatory Drug (IMiD), and one anti-CD38 monoclonal antibody; 6. diagnosed as relapsed/refractory disease or primary refractory disease; 7. The last treatment is ineffective, or the disease progresses within 60 days after the end of the last therapy; 8. Patients must recover from the toxicity of the last therapy (\< grade 2 by CTCAE criteria); 9. ECOG score 1-2 points and the expected survival period ≥ 3 months; 10. Liver, kidney and cardiopulmonary functions meet the following requirements: 1. Total bilirubin ≤ 1.5×ULN, alanine aminotransferase (ALT) ≤ 3 × ULN and aspartate aminotransferase (AST) ≤ 3 × ULN; 2. Serum creatinine ≤ 1.5×ULN, or creatinine clearance ≥ 60 mL/min; 3. Hemoglobin (Hb) ≥ 50 g/L without prior blood transfusion within 7 days; 4. Baseline peripheral oxygen saturation \> 92%; 5. Corrected serum calcium ≤ 12.5 mg/dL (≤ 3.1 mmol/L) or free (ionized, ionic) calcium ≤ 6.5 mg/dL (≤ 1.6 mmol/L); 6. Left ventricular ejection fraction (LVEF) \> 45%, without confirmed pericardiac effusion and abnormal electrocardiography with clinical significance; 7. Without clinically significant pleural effusion; 11. Venous access could be established; without contraindications of apheresis.
Exclusion criteria
1. Previous diagnosis and treatment of other malignancies within 3 years; 2. Patients received previous anti-tumor therapies before apheresis including following therapies: targeted therapies, epigenetics modulation drugs, other drugs or medical devices (invasive) of clinical trials, monoclonal antibodies, cytotoxic agents, PIs, IMiDs, radiotherapy; 3. Central Nervous System (CNS) involvement; 4. Patients with Fahrenheit macroglobulinemia, POEMS syndrome, or primary AL, amyloidosis; 5. Subjects with positive HBsAg or HBcAb positive and peripheral blood HBV DNA titer is higher than the lower limit of detection of the research institution; HCV antibody positive; HIV antibody positive; CMV DNA titer is higher than the lower limit of detection of the research institution; EBV DNA titer is higher than the lower limit of detection of the research institution; 6. Patients have a severe allergic history; 7. Patiens have severe systemic diseases or poor cardiovascular, liver, kidney functions; 8. Acute or chronic graft versus host disease (GvHD) occurs within 6 months before the screening or needs be treated with immunosuppressive agents; 9. Active autoimmune or inflammatory diseases of the nervous system; 10. Patients develop oncology emergencies and need to be treated before screening or infusion; 11. Uncontrolled infections that need antibiotics treatment; 12. Exposure to hematopoietic growth factor of cells within 1-2 weeks before apheresis; 13. Exposure to Corticosteriods or immunosuppressive agents within 2 weeks before apheresis; 14. Patients receive a major surgical operation within 4 weeks before lymphodepletion or do not recover completely before the enrollment; or plan to receive a major surgical operation during the study period; 15. Live attenuated vaccine within 4 weeks before screening; 16. Patients with severe mental illness; 17. Patients are addcited to alcohol or drugs; 18. Pregnant or Lactating Women; Patients and his or her spouse have a fertility plan within two years after CAR-T cell infusion; 19. Other conditions considered inappropriate by the researcher.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Treatment-related Adverse Events | within 2 years after infusion | Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome are graded by American Society for Transplantation and Cellular Therapy (ASTCT) criteria. Other therapy-related adverse events will be recorded and assessed according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE, Version 5.0) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Pharmacokinetics and pharmacodynamics - Tmax | within 2 years after infusion | Tmax will be assessed from CAR T cell infusion to death or last follow-up (censored). |
| Pharmacokinetics and pharmacodynamics - AUC 0-28d | within 2 years after infusion | AUC 0-28d will be assessed from CAR T cell infusion to death or last follow-up (censored). |
| Pharmacokinetics and pharmacodynamics - AUC 0-90d | within 2 years after infusion | AUC 0-90d will be assessed from CAR T cell infusion to death or last follow-up (censored). |
| Pharmacokinetics and pharmacodynamics - AUC 0-inf | within 2 years after infusion | AUC 0-inf will be assessed from CAR T cell infusion to death or last follow-up (censored). |
| Pharmacokinetics and pharmacodynamics - AUC 0-t1/2 | within 2 years after infusion | AUC 0-t1/2 will be assessed from CAR T cell infusion to death or last follow-up (censored). |
| Clinical efficacy of administering BCMA-GPRC5D CAR-T cells in Relapsed/Refractory multiple myeloma | within 2 years after infusion | The rates of stringent complete response (sCRs), complete response (CR), very good partial response (VGPR), partial response (PR), minimal response (MR) will be assessed from CAR T cell infusion to death or last follow-up (censored). |
| Pharmacokinetics and pharmacodynamics - Cmax | within 2 years after infusion | Cmax will be assessed from CAR T cell infusion to death or last follow-up (censored). |
| Clinical benefit rate | within 2 years after infusion | Clinical benefit rate refers to ORR plus MR rate. |
| Duration of Response (DoR) of administering BCMA-GPRC5D CAR-T cells in Relapsed/Refractory multiple myeloma. | within 2 years after infusion | DOR will be assessed from CAR T cell infusion to death or last follow-up (censored). |
| Progress-free survival (PFS) of administering BCMA-GPRC5D CAR-T cells in Relapsed/Refractory multiple myeloma. | within 2 years after infusion | PFS will be assessed from CAR T cell infusion to death or last follow-up (censored). |
| Overall survival (OS) of administering BCMA-GPRC5D CAR-T cells in Relapsed/Refractory multiple myeloma. | within 2 years after infusion | OS will be assessed from CAR T cell infusion to death or last follow-up (censored). |
| Minimal Residual Disease (MRD) | within 2 years after infusion | MRD status will be continuously monitored to assess the negative rate of MRD. |
| Antigen expression in tumor cells at different time points | within 2 years after infusion | Changes in proportion of antigen-positive tumor cells after CAR T cell infusion |
| Overall response rate (ORR) of administering BCMA-GPRC5D CAR-T cells in Relapsed/Refractory multiple myeloma. | within 2 years after infusion | ORR will be assessed from CAR T cell infusion to death or last follow-up (censored). |
Countries
China
Contacts
Primary ContactHeng Mei
Backup ContactChenggong Li
Outcome results
None listed