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

Phase 2

Recruiting

• Conditions: Multiple Myeloma
• Interventions: Drug: Fludarabine + Cyclophosphamide + BCMA-GPRC5D CAR-T Cells

• Registration Number: NCT05998928
• Lead Sponsor: Wuhan Union Hospital, China

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.

Study Timeline

• Study Start: 2023-07-27
• Study First Submitted: 2023-07-28
• Study First Submitted QC: 2023-08-11
• Study First Posted: 2023-08-21
• Status Verified: 2023-11
• Last Update Submitted: 2023-11-08
• Last Update Posted: 2023-11-13
• Primary Completion: 2025-07-27
• Study Completion: 2026-07-27

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 10

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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Fludarabine + Cyclophosphamide + BCMA-GPRC5D CAR-T Cells	Fludarabine + Cyclophosphamide + BCMA-GPRC5D CAR-T Cells	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.

Primary Outcome Measures

Name	Time	Method
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 Outcome Measures

Name	Time	Method
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).
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).
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).
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).
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
Minimal Residual Disease (MRD)	within 2 years after infusion	MRD status will be continuously monitored to assess the negative rate of MRD.

Trial Locations

Locations (1)

Union Hospital, Tongji Medical College, Huazhong University of Science and Technology; 🇨🇳 Wuhan, Hubei, China