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

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

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.

Study Overview

• Status: Recruiting
• Conditions: Multiple Myeloma
• Intervention / Treatment: Drug: Fludarabine + Cyclophosphamide + BCMA-GPRC5D CAR-T Cells

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 Type: Interventional
• Enrollment (Estimated): 10
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Heng Mei; Phone Number: 027-8572600; Email: hmei@hust.edu.cn
• Study Contact Backup: Name: Chenggong Li; Phone Number: 18108675948; Email: chenggongli@hust.edu.cn

Study Locations

• China
  • Hubei
    • Wuhan, Hubei, China, 430022
      • Recruiting
      • Union Hospital, Tongji Medical College, Huazhong University of Science and Technology
      • Principal Investigator: Heng Mei, M.D., Ph.D
      • Contact: Chenggong Li; Email: chenggongli@hust.edu.cn
      • Contact: Heng Mei, M.D., Ph.D; Email: hmei@hust.edu.cn

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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.	Drug: Fludarabine + 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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Wuhan Union Hospital, China
• Collaborators: Guangzhou Bio-gene Technology Co., Ltd
• Investigators: Principal Investigator: Heng Mei, Wuhan Union Hospital, China

Publications and helpful links

General Publications

• Mailankody S, Devlin SM, Landa J, Nath K, Diamonte C, Carstens EJ, Russo D, Auclair R, Fitzgerald L, Cadzin B, Wang X, Sikder D, Senechal B, Bermudez VP, Purdon TJ, Hosszu K, McAvoy DP, Farzana T, Mead E, Wilcox JA, Santomasso BD, Shah GL, Shah UA, Korde N, Lesokhin A, Tan CR, Hultcrantz M, Hassoun H, Roshal M, Sen F, Dogan A, Landgren O, Giralt SA, Park JH, Usmani SZ, Riviere I, Brentjens RJ, Smith EL. GPRC5D-Targeted CAR T Cells for Myeloma. N Engl J Med. 2022 Sep 29;387(13):1196-1206. doi: 10.1056/NEJMoa2209900.
• Fernandez de Larrea C, Staehr M, Lopez AV, Ng KY, Chen Y, Godfrey WD, Purdon TJ, Ponomarev V, Wendel HG, Brentjens RJ, Smith EL. Defining an Optimal Dual-Targeted CAR T-cell Therapy Approach Simultaneously Targeting BCMA and GPRC5D to Prevent BCMA Escape-Driven Relapse in Multiple Myeloma. Blood Cancer Discov. 2020 Sep;1(2):146-154. doi: 10.1158/2643-3230.BCD-20-0020.

Study record dates

Study Major Dates

• Study Start (Actual): July 27, 2023
• Primary Completion (Estimated): July 27, 2025
• Study Completion (Estimated): July 27, 2026

Study Registration Dates

• First Submitted: July 28, 2023
• First Submitted That Met QC Criteria: August 11, 2023
• First Posted (Actual): August 21, 2023

Study Record Updates

• Last Update Posted (Actual): November 13, 2023
• Last Update Submitted That Met QC Criteria: November 8, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Immunoproliferative Disorders; Hematologic Diseases; Hemorrhagic Disorders; Hemostatic Disorders; Paraproteinemias; Blood Protein Disorders; Multiple Myeloma; Neoplasms, Plasma Cell; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Cyclophosphamide; Fludarabine
• Other Study ID Numbers: BCMA-GPRC5D CAR-T-cells

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No