To Evaluate the Safety and Efficacy of Human Derived Anti-BCMA CAR-T Injection for Subjects With R/R MM

Study Overview
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Brief Summary
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This study is a single-arm, open-label, dose-escalation trial to explore the safety, tolerability and pharmacokinetic/pharmacodynamics characteristics of Human Derived anti-BCMA CAR-T Injection , and to preliminarily observe the efficacy of the trial drug in patients with relapsed/refractory multiple myeloma.

Detailed Description
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Subjects withe relapsed/refractory multiple myeloma can participate if all eligibility criteria are met. Tests required to determine eligibility including disease assessments, a physical exam, Electrocardiograph, Computed tomography（CT）/Magnetic Resonance Imaging(MRI)/Positron Emission Tomography（PET）,liver/renal function tests, complete blood count with differential and complete metabolic profile and etc.. Subjects will receive precondtioning chemotherapy prior to the infusion of BCMA CAR- T cells. After the infusion, subjects will be followed for adverse events pharmacokinetic/pharmacodynamics characteristics, efficacy, of BCMA CAR-T cells. Study procedures may be performed while hospitalized.

Official Title
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A Early Phase 1 Clinical Trial To Evaluate the Safety and Efficacy of Human Derived Anti-BCMA CAR-T Injection for Subjects With Relapsed/Refractory Multiple Myeloma

Conditions
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Multiple Myeloma

Intervention / Treatment
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* Drug: Human Derived anti-BCMA CAR-T Injection


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects must meet all of the following criteria to be enrolled: Subjects volunteer to participate in clinical trails, understand and inform the trials and sign informed consent form, be willing to complete all the trial procedures; 18 to 75 years old (including cut-off value), Male and female; Expected survival > 12 weeks; Previously diagnosed as multiple myeloma by IMWG updated criteria (2014); One of the following indicators is satisfied: Serum M protein: for immunoglobulin G (IgG) type , M protein≥ 10 g/L, or for immunoglobulin A (IgA) type , M protein > 5g/L, or for immunoglobulin D (IgD) type , M protein, IgD exceeds upper limit of normal range. Urine M protein ≥ 200 mg/24h; Serum free light chain ≥ 100 mg/L and Serum free light chain ratio is abnormal ; Patients with relapsed/refractory multiple myeloma. Relapsed is defined as: Patients have disease progression after at least three-line treatment regimens. Patients previously received at least 3 different mechanisms treatment regimens for multiple myeloma, including protease inhibitors and immunomodulators; Refractory is defined as: Patients who achieved minimal response(MR) or above was never achieved in previous treatment; MR or above was achieved in previous treatment, but disease progression occurred during subsequent treatment or within 60 days after the last treatment. ECOG score 0-2; Liver, kidney and cardiopulmonary functions meet the following requirements: Creatinine clearance (estimated by Cockcroft Gault formula) ≥ 40 mL/min; Left ventricular ejection fraction >50%; Baseline peripheral oxygen saturation >95%; Total bilirubin ≤ 2×ULN; Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 × ULN; The venous access required for collection can be established and leukepheresis can be carriedaccording to the judgement of investigators. Exclusion Criteria: Any one of the following conditions cannot be selected as a subject： Accompanied by other uncontrolled malignancies; Subjects with positive Hepatitis B surface antigen (HBsAg) or Hepatitis B core antibody (HBcAb) and peripheral blood Hepatitis B virus(HBV) DNA titer is ≥500IU/mL; hepatitis C virus (HCV) antibody positive and peripheral blood HCV RNA positive; human immunodeficiency virus(HIV) antibody positive; syphilis primary screening antibody positive; Any instability of systemic disease, including but not limited to unstable angina, cerebrovascular accident, or transient cerebral ischemic (within 6 months prior to screening), myocardial infarction (within 6 months prior to screening), congestive heart failure （New York heart association (NYHA) classification ≥ III), need drug therapy of severe arrhythmia, liver, kidney, or metabolic disease; Patients who are accounted to be not appropriate for this trail by investigator; Pregnant or lactating woman, and female subject who plans to have a pregnancy within 1 year after cell transfusion, or male subject whose partner plans to have a pregnancy within 1 year after cell transfusion; Received CAR-T treatment or other gene therapies before enrollment; Those who failed to sign informed consent form or comply with the research procedures; Unwilling or unable to comply with research requirements; Have had severe immediate hypersensitivity reactions to any drugs used in this research; Active or uncontrollable infection requiring systemic therapy within 14 days prior to enrollment; In the past two years, the terminal organ was damaged due to autoimmune diseases (such as Crohn's disease, rheumatoid arthritis, systemic lupus erythematosus), or the systemic use of immunosuppressive or other systemic disease control drugs was required; Patients with symptoms of central nervous system.

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: Human Derived anti-BCMA CAR-T Injection<br>Single administration：1.0×10^6 CAR+T, 3.0×10^6 CAR+T, 6.0×10^6 CAR+T | Drug: Human Derived anti-BCMA CAR-T Injection<br>* Autologous genetically modified anti-BCMA CAR transduced T cells<br>* Other names: BCMA CAR-T;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose limited toxicity(DLT) | Safety Indicator | 28 days post infusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics parameters - Maximum CAR level in blood and CAR level in bone marrow(Cmax) | Effectiveness Metrics | 2 years post infusion | 
| Pharmacokinetics parameters -Time to peak CAR level in blood (Tmax) | Effectiveness Metrics | 2 years post infusion | 
| Pharmacokinetics parameters - 28-day Area under the curve of the CAR level in blood(AUC0-28) | Effectiveness Metrics | 2 years post infusion | 
| Pharmacodynamics characteristics - Cytokines Concentrations,cytokines level in blood | Effectiveness Metrics | 2 years post infusion | 
| Pharmacodynamics characteristics -Clonal bone marrow plasma cells level | Effectiveness Metrics | 2 years post infusion | 
| Overall Response Rate (ORR) at 3 month post infusion | ORR defined as proportion of subjects who achieved Partial remission(PR) or better according to the International Myeloma Working Group response criteria (2016) (IMWG 2016) as determined by an Investigator assessment at 3 month post infusion. | 3 month post infusion | 
| Percentage of Subjects With Negative Minimal Residual Disease (MRD) | MRD negative rate is defined as the proportion of subjects who achieve MRD negative status | 2 years post infusion | 
| Duration of Subjects With Negative Minimal Residual Disease (MRD) | MRD duration will calculated among MRD negative responders fom the date of initial MRD negative to the date of first documented evidence of MRD positive, as defined in the IMWG criteria (2016). | 2 years post infusion | 
| Number of Subjects with Adverse Events | Adverse event is any untoward medical event that occurs in a subject administered an investigational drug. | 2 years post infusion | 
| Change from Baseline in Perform Status as Measured by Eastern Cooperative Oncology Group（ECOG）Score（0-4） | Eastern Cooperative Oncology Group（ECOG） Performance Status Score（0-4） will be assessed by the inverstigator at baseline and the respective time point, higher scores mean a worse performance status. | 2 years post infusion | 
| Change from Baseline in complete blood count with differential and blood biochemical examination | complete blood count with differential and blood biochemical examination will be assessed by the investigator at the respective time point. | 2 years post infusion | 
| Change from Baseline in Physical Exam | physical exam will be assessed by the inverstigator at the respective time poin. | 2 years post infusion | 
| Progression-free Survival (PFS) | PFS defined as time from date of initial infusion of CAR-T to date of first disease progression according to IMWG criteria (2016) , or death due to any cause, whichever occurs first. | 2 years post infusion | 
| Overall Survival (OS) | OS is measured from the date of the initial infusion of CAR-T to the date of the subject's death. | 2 years post infusion | 
| Duration of Response (DOR) | DOR will be calculated among responders (with a PR or better response) from the date of initial response (PR or better) to the date of first documented evidence of progressive disease, as defined in the IMWG criteria (2016). | 2 years post infusion | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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BCMA, CAR-T, multiple myeloma, Relapsed /Refractory