T Cells Expressing a Bispecific CAR Targeting CS1 and BCMA in Relapsed/Refractory Multiple Myeloma

CS1+ or BCMA+ Multiple Myeloma Clinical Trial

Official title:

Safety and Efficacy of the Bispecific CAR T Therapy Targeting CS1 and BCMA in Patients With Relapsed/ Refractory Multiple Myeloma: a Single-center, Open-label, Single-arm Clinical Study

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04662099
• Other study ID #: CS1+BCMA bispecific CART
• Status: Recruiting
• Phase: Phase 1
• Start date: March 25, 2020
• Est. completion date: December 30, 2023

Study information

• Verified date: August 2023
• Source: Wuhan Union Hospital, China
• Contact: Heng Mei, M.D., Ph.D
• Phone: 86-13986183871
• Email: hmei[@]hust.edu.cn
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This is a single-center, open-label, single-arm study to evaluate the safety and efficacy of the bispecific CAR T cells targeting CS1 and BCMA in patients with relapsed or refractory multiple myeloma.

Description:

• Multiple myeloma(MM) is one of the most common hematological malignancies with substantial morbidity and mortality.

• In recent years, several new therapies have prolonged survival of patients with MM, but it is still an incurable malignancy of plasma cells.

• B-cell maturation antigen (BCMA) is expressed by normal and malignant plasma cells and a small subset of B cells. This specific expression pattern makes BCMA an ideal target antigen for immunotherapies in MM.

• BCMA-targeted chimeric antigen receptor (CAR) T cells have exhibited significant efficacy in MM, but relapse due to single-target escape or poor in vivo persistence has been reported.

• Dual-targets or sequential infusion have been proposed to reduce relapse and improve outcomes post BCMA-specific CAR T therapies.

• CS1 is expressed on pro-B cells and plasma cells especially malignant ones and some evidence suggests it plays a role in stromal cell interaction in the BM tumour microenvironment.

• We have constructed a bispecific CAR containing anti-CS1 single chain variable region (scFv) and an anti-BCMA scFv in 4-1BB-containing second-generation formats.

• The bispecific CAR T cells have exhibited potent cytotoxicity in various BCMA+ or/and CS1+ MM cells and can effectively eradicate MM cells in xenograft mice models.

• This study aims to evaluate prelimary safety and efficacy of the CS1&BCMA CAR T cells in patients with relapsed or refractory MM.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 24
• Est. completion date: December 30, 2023
• Est. primary completion date: December 30, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

Inclusion Criteria:

Each potential subject must meet all of the following criteria to be enrolled in the study:

1. Aged 18-78 years old, males or females.

2. Relapsed or refractory multiple myeloma according to IMWG diagnostic criteria.

3. Received at least 2 prior lines of treatment for multiple myeloma, including a proteasome inhibitor and an immunomodulatory drug.

4. Detectable MM cells in bone marrow by conventional morphologic methods or flow cytometry, and positive expression of CS1 or BCMA on MM cells as confirmed by immunohistochemistry or flow cytometry.

5. Measurable diseases at screening as defined by any of the following:

• Serum M-protein level =1.0g/dL;

• Urine M-protein level =200mg/24 hours;

• Serum immunoglobulin free light chain(FLC) =10 mg/dL provided abnormal FLC ratio.

6. Recovery to grade 1 or baseline of toxicities due to prior treatment, excluding hematologic toxicities and toxicity of no clinical significance, like alopecia.

7. ECOG Performance Status 0 ~ 2 (ECOG status of larger than 2 points caused by MM osteolytic destruction is accepted).

8. Good organ function at screening as defined by any of the following:

• AST and ALT = 2.5×upper limit of normal (ULN);

• Total bilirubin= 2.0×ULN;

• Creatinine clearance =30 mL/min/1.73m2;

• Ejection fraction of heart =50%, and no clinically significant abnormal ECG findings.

9. Clinical laboratory values meeting the following criteria at screening:

• Absolute Neutrophil Count(ANC) =1.0×10^9/L;

• Platelets =30×10^9/L;

• Absolute Lymphocyte Count =1.0×10^8/L;

• Hemoglobin(Hb) =6.0g/dL.

10. Women of childbearing potential must have a negative pregnancy test at screening.

11. Patients with extramedullary lesions were eligible.

12. Patients who received prior allogeneic or autologous stem cell transplantation at least three months before screening were eligible.

13. Sign the informed consent voluntarily.

Exclusion Criteria:

Any potential subject who meets any of the following criteria will be excluded from participating in the study:

1. Evidence of serious viral, bacterial, or uncontrolled systemic fungal infection.

2. Seropositive for human immunodeficiency virus (HIV) antibody.

3. Seronegative for hepatitis B antigen or a known history of hepatitis B.

4. Hepatitis C (anti-hepatitis C virus [HCV] antibody positive or HCV-RNA quantitation positive) or a known history of hepatitis C.

5. Systemic corticosteroid therapy of greater than 5 mg/day of prednisone or equivalent dose within 2 weeks prior to apheresis.

6. Active autoimmune disease or a history of autoimmune disease within 3 years.

7. The following cardiac conditions: Myocardial infarction or coronary artery bypass graft =6 months prior to enrollment; History of clinically significant ventricular arrhythmia or unexplained; New York Heart Association stage III or IV congestive heart failure.

8. A history of epilepsy or other central nervous system diseases or altered mental status.

9. Known life-threatening allergies, hypersensitivity, or intolerance to CAR-T cells or relevant lymphodepleting regimens (cyclophosphamide and fludarabine).

10. Pregnant or breast-feeding, or planning to become pregnant while enrolled in this study or within one year after receiving study treatment.

11. Any uncontrolled diseases, other than multiple myeloma, that may lead to abnormal death.

12. Being participating in other intervention studies.

13. Other cases excluded by the Investigators.

Related Conditions & MeSH terms

• CS1+ or BCMA+ Multiple Myeloma
• Multiple Myeloma
• Neoplasms, Plasma Cell

Intervention

Biological:
• Conditioning chemotherapy followed by CAR T cell infusion
Conditioning chemotherapy: Cyclophosphamide 250 mg/m^2 and fludarabine 30 mg/m^2 IV infusion on days -5, -4, and -3 CAR T cells infusion: 0.75x10^6-3.0X10^6 CAR+ T cells per kg of recipient bodyweight. if DLTs don't occur at the dose of 3.0X10^6 CAR+ T cells per kg, the investigators will discuss whether to try higher dose.

Locations

Country	Name	City	State
China	Union Hospital, Tongji Medical College, Huazhong University of Science and Technology	Wuhan	Hubei

Sponsors (2)

Lead Sponsor	Collaborator
Wuhan Union Hospital, China	Wuhan Si'an Medical Technology Co., Ltd

Country where clinical trial is conducted

China, 

References & Publications (2)

Mikkilineni L, Kochenderfer JN. CAR T cell therapies for patients with multiple myeloma. Nat Rev Clin Oncol. 2021 Feb;18(2):71-84. doi: 10.1038/s41571-020-0427-6. Epub 2020 Sep 25. — View Citation

Zah E, Nam E, Bhuvan V, Tran U, Ji BY, Gosliner SB, Wang X, Brown CE, Chen YY. Systematically optimized BCMA/CS1 bispecific CAR-T cells robustly control heterogeneous multiple myeloma. Nat Commun. 2020 May 8;11(1):2283. doi: 10.1038/s41467-020-16160-5. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	In vivo expansion and survival of CS1&BCMA bispecific CAR T cells	In vivo (bone marrow and peripheral blood) rate and quantity will be determined by using flow cytometry and qPCR.	2 years after infusion
Primary	Incidence of Treatment-related Adverse Events	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	Overall response rate(ORR) and complete response rate(CRR) of administering T cells Expressing a bispecific CAR Targeting CS1 and BCMA in Relapsed/Refractory Multiple Myeloma	OR and CRR will be assessed from CAR T cell infusion to death or last follow-up (censored).	2 years after infusion
Secondary	Overall survival(OS), duration of Response(DOR), progress-free survival(PFS) of administering T cells Expressing a bispecific CAR Targeting CS1 and BCMA in Relapsed/Refractory Multiple Myeloma	OS, PFS and DOR will be assessed from CAR T cell infusion to death or last follow-up (censored).	2 years after infusion