A Clinical Study to Evaluate the Safety and Efficacy of BCMA-GPRC5D CAR-T in Patients With Relapsed/Refractory Multiple Myeloma Who Received Three or More Lines of Therapy

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Clinical Study to Evaluate the Safety and Efficacy of BCMA-GPRC5D CAR-T in Patients With R/R MM Who Received Three or More Lines of Therapy

Conditions
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Multiple Myeloma

Intervention / Treatment
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* Drug: Fludarabine + Cyclophosphamide + BCMA-GPRC5D CAR-T Cells


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient or his or her legal guardian voluntarily participates in and signs an informed consent form; Aged ≥ 18 years and ≤ 75 years; Diagnosed as Multiple Myeloma (MM) according to the international standard for multiple myeloma (IMWG); 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; 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; diagnosed as relapsed/refractory disease or primary refractory disease; The last treatment is ineffective, or the disease progresses within 60 days after the end of the last therapy; Patients must recover from the toxicity of the last therapy (< grade 2 by CTCAE criteria); ECOG score 1-2 points and the expected survival period ≥ 3 months; Liver, kidney and cardiopulmonary functions meet the following requirements: Total bilirubin ≤ 1.5×ULN, alanine aminotransferase (ALT) ≤ 3 × ULN and aspartate aminotransferase (AST) ≤ 3 × ULN; Serum creatinine ≤ 1.5×ULN, or creatinine clearance ≥ 60 mL/min; Hemoglobin (Hb) ≥ 50 g/L without prior blood transfusion within 7 days; Baseline peripheral oxygen saturation > 92%; Corrected serum calcium ≤ 12.5 mg/dL (≤ 3.1 mmol/L) or free (ionized, ionic) calcium ≤ 6.5 mg/dL (≤ 1.6 mmol/L); Left ventricular ejection fraction (LVEF) > 45%, without confirmed pericardiac effusion and abnormal electrocardiography with clinical significance; Without clinically significant pleural effusion; Venous access could be established; without contraindications of apheresis. Exclusion Criteria: Previous diagnosis and treatment of other malignancies within 3 years; 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; Central Nervous System (CNS) involvement; Patients with Fahrenheit macroglobulinemia, POEMS syndrome, or primary AL, amyloidosis; 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; Patients have a severe allergic history; Patiens have severe systemic diseases or poor cardiovascular, liver, kidney functions; Acute or chronic graft versus host disease (GvHD) occurs within 6 months before the screening or needs be treated with immunosuppressive agents; Active autoimmune or inflammatory diseases of the nervous system; Patients develop oncology emergencies and need to be treated before screening or infusion; Uncontrolled infections that need antibiotics treatment; Exposure to hematopoietic growth factor of cells within 1-2 weeks before apheresis; Exposure to Corticosteriods or immunosuppressive agents within 2 weeks before apheresis; 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; Live attenuated vaccine within 4 weeks before screening; Patients with severe mental illness; Patients are addcited to alcohol or drugs; Pregnant or Lactating Women; Patients and his or her spouse have a fertility plan within two years after CAR-T cell infusion; Other conditions considered inappropriate by the researcher.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Fludarabine + Cyclophosphamide + BCMA-GPRC5D CAR-T Cells<br>Patients will receive lymphodepletion chemotherapy with fludarabine (30 mg/m2 body surface area) plus cyclophosphamide (300 mg/m2 body surface area) for 3 consecutive days during D-7 to D-3, followed by the infusion of BCMA-GPRC5D CAR-T cells at a single dose of 4.0×10^6/kg ± 50%/kg for one day. | Drug: Fludarabine + Cyclophosphamide + BCMA-GPRC5D CAR-T Cells<br>* 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<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Treatment-related Adverse Events | 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) | within 2 years after infusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics and pharmacodynamics - Cmax | Cmax will be assessed from CAR T cell infusion to death or last follow-up (censored). | within 2 years after infusion | 
| Pharmacokinetics and pharmacodynamics - Tmax | Tmax will be assessed from CAR T cell infusion to death or last follow-up (censored). | within 2 years after infusion | 
| Pharmacokinetics and pharmacodynamics - AUC 0-28d | AUC 0-28d will be assessed from CAR T cell infusion to death or last follow-up (censored). | within 2 years after infusion | 
| Pharmacokinetics and pharmacodynamics - AUC 0-90d | AUC 0-90d will be assessed from CAR T cell infusion to death or last follow-up (censored). | within 2 years after infusion | 
| Pharmacokinetics and pharmacodynamics - AUC 0-inf | AUC 0-inf will be assessed from CAR T cell infusion to death or last follow-up (censored). | within 2 years after infusion | 
| Pharmacokinetics and pharmacodynamics - AUC 0-t1/2 | AUC 0-t1/2 will be assessed from CAR T cell infusion to death or last follow-up (censored). | within 2 years after infusion | 
| Clinical efficacy of administering BCMA-GPRC5D CAR-T cells in Relapsed/Refractory multiple myeloma | 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). | within 2 years after infusion | 
| Overall response rate (ORR) of administering BCMA-GPRC5D CAR-T cells in Relapsed/Refractory multiple myeloma. | ORR will be assessed from CAR T cell infusion to death or last follow-up (censored). | within 2 years after infusion | 
| Clinical benefit rate | Clinical benefit rate refers to ORR plus MR rate. | within 2 years after infusion | 
| Duration of Response (DoR) of administering BCMA-GPRC5D CAR-T cells in Relapsed/Refractory multiple myeloma. | DOR will be assessed from CAR T cell infusion to death or last follow-up (censored). | within 2 years after infusion | 
| Progress-free survival (PFS) of administering BCMA-GPRC5D CAR-T cells in Relapsed/Refractory multiple myeloma. | PFS will be assessed from CAR T cell infusion to death or last follow-up (censored). | within 2 years after infusion | 
| Overall survival (OS) of administering BCMA-GPRC5D CAR-T cells in Relapsed/Refractory multiple myeloma. | OS will be assessed from CAR T cell infusion to death or last follow-up (censored). | within 2 years after infusion | 
| Minimal Residual Disease (MRD) | MRD status will be continuously monitored to assess the negative rate of MRD. | within 2 years after infusion | 
| Antigen expression in tumor cells at different time points | Changes in proportion of antigen-positive tumor cells after CAR T cell infusion | within 2 years after infusion |