A Study of CAR-T Cells Targeting GPRC5D in the Treatment of r/r Multiple Myeloma

Study Overview
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Brief Summary
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This is a single-arm, open-label, dose-escalation study to evaluate the safety, tolerability, cellular kinetics and initial efficacy of CAR-T cell therapy targeting GPRC5D in multiple myeloma subjects who have failed the standard treatments.

Official Title
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A Single Arm, Open Label Clinical Study of CAR-T Cells Targeting GPRC5D in the Treatment of Relapsed / Refractory Multiple Myeloma(POLARIS)

Conditions
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Multiple Myeloma

Intervention / Treatment
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* Drug: GPRC5D-CAR-T


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: The subject can understand and have the ability to sign an informed consent form; Male or female subjects, aged 18-75 years; The expected survival period is not less than 12 weeks; ECOG score ≤ 2 ; Diagnosed as multiple myeloma according to the IMWG standard in 2018; The expression of GPRC5D in bone marrow plasma cells is more than 20%, or it is positive in tumor tissue by immunohistochemistry. One of the following criteria must be detected: If IgG type MM, serum M protein ≥10g/L; if IgA, IgD, IgE or IgM type MM, serum M protein ≥5g/L; Or urine M protein level ≥200mg/24h; Or light chain type MM, serum free light chain (sFLC) ≥ 100mg / L and K/ λ FLC ratio is abnormal; Or there are extramedullary lesions; Subjects who have received at least 3 different mechanism drugs (including chemotherapy, protease inhibitors, immunosuppressive agents, etc.) have failed treatments, or have progressed or recurred during the last treatment or within 6 months after the end of treatment ; Lung function is normal, and oxygen saturation is greater than 92%; No heart disease or coronary heart disease, echocardiogram showed normal diastolic function, left ventricular ejection fraction (LVEF) ≥50%, and no serious arrhythmia; Liver function: TBIL<3×ULN, AST<2.5×ULN, ALT<2.5ULN; Renal function: creatinine clearance rate (estimated by Cockcroft Gault formula) ≥ 30 mL/min; The blood routine meets the following standards: Lymphocyte count>0.5×10e9/L; Neutrophils ≥1.0×10e9/L; Hemoglobin ≥80g/L; Platelet ≥75×10e9/L From the use of study drug to 2 years after treatment, male subjects or female subjects of childbearing age must agree and be able to take effective contraceptive measures. Exclusion Criteria: Pregnant or breastfeeding; HBsAg or HBcAb are positive, and the quantitative detection of HBV DNA in peripheral blood is more than 100 copies / L; HCV antibody and HCV RNA in peripheral blood are positive; HIV antibody positive; Syphilis antibody is positive in the first screening; Any unstable systemic disease: including but not limited to unstable angina, cerebrovascular accident or transient cerebral ischemia (within 6 months before screening), myocardial infarction (within 6 months before screening), congestive heart failure (New York Heart Association [NYHA] classification ≥ grade III), severe arrhythmia with poor drug control, liver, kidney or metabolic diseases; Had hypersensitivity or intolerance to any drug used in this study; Patients who received anti-cancer chemotherapy or other medications within 2 weeks before screening; Uncontrolled malignant tumors except MM, excluding malignant tumors that received radical treatment and no active disease was found within 3 years before enrollment; Clinically significant central nervous system diseases, such as epilepsy, cerebrovascular ischemia/hemorrhage, dementia, cerebellar disease, psychosis, active central nervous system involvement or cancerous meningitis; In the past two years, autoimmune diseases (such as Crohn's disease, rheumatoid arthritis, systemic lupus erythematosus) caused damage to terminal organs, or required systemic application of immunosuppressive or other drugs; Severe active viral, bacterial or uncontrolled systemic fungal infections; Hereditary bleeding / coagulation diseases, history of non traumatic bleeding or thromboembolism, other diseases that may increase the risk of bleeding, etc; Patients who received autologous hematopoietic stem cell transplantation (ASCT) within 8 weeks before screening, or who plan to undergo ASCT during the study period; Patients received allogeneic stem cell therapy; Any unsuitable to participate in this trial judged by the investigator.

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: Treatment Group<br>This is a open label, single arm clinical trial. | Drug: GPRC5D-CAR-T<br>* After enrollment, subjects complete the PBMC apheresis, then complete the Lymphocyte clearance, and then receive the dose climbing test: 1×10e6/kg，3×10e6/kg，6×10e6/kg.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose limited toxicity (DLT) | Dose limited toxicity | From date of initial treatment to Day 28 post GPRC5D CAR-T infusion. | 
| AE and SAE | Adverse event and serious adverse event | From admission to the end of the follow-up, up to 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Concentration of CAR-T cells | In peripheral blood and bone marrow | From admission to the end of the follow-up, up to 2 years | 
| Objective Response Rate, ORR | Proportion of subjects with complete or partial remission | In 3 months of GPRC5D CAR-T cell infusion | 
| Disease control rate, DCR | The percentage of patients with remission and stable disease after treatment in the total evaluable cases. | From Day 28 GPRC5D CAR-T infusion up to 2 years | 
| Duration of remission, DOR | The time from the first assessment of remission or partial remission of the tumor to the first assessment of disease progression or death from any cause; | 24 months post GPRC5D CAR-T cells infusion | 
| Progression-free survival, PFS | The time from cell reinfusion to the first assessment of tumor progression or death from any cause | 24 months post GPRC5D CAR-Tcells infusion | 
| Overall survival, OS | The time from the cell reinfusion to death due to any cause. | From GPRC5D CAR-T infusion to death，up to 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CAR-T, GPRC5D, Multiple Myeloma