A Study of CAR-GPRC5D in Patients With Relapsed/Refractory Multiple Myeloma or Plasma Cell Leukemia

Study Overview
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Brief Summary
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This study is a single-center, open, dose-escalation study to observe the safety and efficacy of different doses of CAR-GPRC5D in patients with R/R MM or Plasma Cell Leukemia.

Detailed Description
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Leukapheresis procedure will be performed to manufacture CAR-GPRC5D chimeric antigen receptor (CAR) modified T cells. Bridging therapy is allowed between PBMC collection and lymphodepletion. Lymphodepletion with fludarabine and cyclophosphamide was performed for three consecutive days. After 1-day rest, subjects will receive a single dose infusion of CAR-GPRC5D at 0.5, 1.0, or 2.0 x 10^6 CAR+ T cells/Kg. Subjects will be followed in the study for a minimum of 2 years after infusion. Long-term follow-up for lentiviral vector safety will be followed for up to 15 years after infusion.

Official Title
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An Exploratory Study of Fully Human Anti-GPRC5D Chimeric Antigen Receptor T Cells (CAR-GPRC5D) in Patients With Relapsed/Refractory Multiple Myeloma or Plasma Cell Leukemia

Conditions
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Relapsed/Refractory Multiple Myeloma, Plasma Cell Leukemia

Intervention / Treatment
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* Drug: CAR-T (CAR-GPRC5D)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects must satisfy all the following criteria to be enrolled in the study: age 18 to 75 years old, male or female. Subjects have had at least 3 prior lines of therapy including chemotherapy based on proteasome inhibitors (PIs) and immunomodulatory agents (IMiDs). According to the International Myeloma Working Group (IMWG) consensus (2016) standard on multiple myeloma, the disease has recurred, progressed or is refractory, or according to the IMWG consensus (2013) standard on plasma cell leukemia (Appendix 4), the disease appears relapse, progress or refractory; Evidence of cell membrane GPRC5D expression, as determined by a validated immunohistochemistry (IHC) or flow cytometry of tumor tissue (e.g., bone marrow biopsies, or plasmacytoma). The subjects should have measurable disease based on at least one of the following parameters: The proportion of primitive immature or monoclonal plasma cells detected by bone marrow cytology, bone marrow biopsy, or flow cytometry is ≥ 10%. Serum M-protein ≥ 10 g/L for IgG type, serum M-protein ≥ 5 g/L for other types, such as IgA, IgD, IgM, IgE. Urine M-protein ≥ 200 mg/24 hrs. For those whose Serum or Urine M-protein does not meet the measurable criteria but the light chain type, serum free light chain (sFLC) : involved sFLC level ≥ 10mg/dL (100 mg/L) provided serum FLC ratio is abnormal. In subjects with extramedullary myeloma, if there are no other evaluable lesions, require extramedullary lesions with a maximum diameter of ≥2cm ECOG performance score 0-2. Estimated life expectancy ≥ 12 weeks. Subjects should have adequate organ function: Hematology: Absolute neutrophil count (ANC) ≥1×10^9 /L (prior use of growth factor support is permitted, but subjects must not have received supportive treatment within 7 days prior to laboratory examination); absolute lymphocyte count (ALC) ≥0.3×10^9 /L; platelets ≥40×10^9 /L (subjects must not have received blood transfusion support within 7 days prior to laboratory examination); hemoglobin ≥60 g/L (subjects must not have received transfusion of red blood cells [RBC] within 7 days prior to laboratory examination; the use of recombinant human erythropoietin is permitted). Liver function: Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5×upper limit of normal (ULN); total serum bilirubin ≤ 1.5×ULN. Renal function: Creatinine clearance rate (CrCl) calculated according to Cockcroft-Gault formula ≥ 40 ml/min. Coagulation function: Fibrinogen ≥ 1.0 g/L; activated partial thromboplastin time (APTT) ≤ 1.5×ULN, prothrombin time (PT) ≤1.5×ULN. SpO2 > 91%. Left ventricular ejection fraction (LVEF) ≥ 50%. The subject and his/her spouse agree to use an effective contraceptive tool or medication (excluding safety period contraception) for one year from the date of the subject's informed consent to the date of CAR T cell infusion. Subject must sign the informed consent form approved by ethics board in person before starting any screening procedure. Exclusion Criteria: The presence of any of the following will exclude a subject from enrollment: Subjects who are known to have GVHD or need long-term immunosuppressive therapy. Subjects have received any anti-cancer treatment as follows: monoclonal antibody for treating multiple myeloma within 21 days before leukapheresis, or cytotoxic therapy or proteasome inhibitors within 14 days before leukapheresis, or immunomodulatory agents within 7 days before leukapheresis. or anti-tumor treatments other than those listed above within 30 days before leukapheresis. Subjects who were receiving a used therapeutic dose of corticosteroid treatment (defined as prednisone or equivalent > 20mg) within 7 days prior to screening, except for physiological alternatives, inhalation, or topical use. Subjects with hypertension that cannot be controlled by medication. Subjects with serious heart disease: including but not limited to unstable angina, myocardial infarction (within 6 months prior to screening), congestive heart failure (NYHA classification ≥III), and severe arrhythmias. Subjects with systemic diseases that the investigator determined to be unstable include, but are not limited to, severe liver and kidney or metabolic diseases requiring medical treatment. Subjects with second malignancies in addition to MM within the past 5 years before the screening, exceptions to this criterion: successfully treated cervical carcinoma in situ and non-metastatic basal or squamous cell skin carcinoma, local prostate cancer after radical surgery, and ductal carcinoma in situ of the breast after radical surgery. Subjects with a history of organ transplantation. Subjects have received major surgery within 2 weeks prior to leukapheresis or plan to receive surgery during the study or within 2 weeks after the study treatment (excluding local anesthesia). Subjects participated in another interventional clinical study 1 months before signing the informed consent (ICF); Subjects with any uncontrolled active infection needed to receive systemic therapy within 7 days before leukapheresis collection (excluding # CTCAE grade 2 urogenital infection and upper respiratory infection). Positive for any of the following tests: Hepatitis B virus (HBV) surface antigen (HBsAg) or hepatitis B core antibody-positive and detectable HBV DNA in peripheral blood; Hepatitis C virus (HCV) antibody and hepatitis C virus RNA in peripheral blood; Human immunodeficiency virus (HIV) antibody; Cytomegalovirus (CMV) DNA; Treponema Pallidum antibody Pregnant or lactating women. Subjects with mental illness or consciousness disorder or disease of the central nervous system Other conditions that researchers consider inappropriate for inclusion.

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
Interventional Model Description: This study sampled the 3+3 dose-escalation design, and set up three dose-increasing dose groups of 0.5×10^6 CAR-T/Kg, 1.0×10^6 CAR-T/Kg, 2.0×10^6 CAR-T/Kg, and subjects will receive a single infusion of CAR-GPRC5D/ single dose. Each dose group level will include 3-6 subjects, and the total number of subjects depends on increased dose levels. The estimated number of enrollment at this stage will be 9-18 cases in total. This study is to observe the characteristics of dose-limiting toxicity (DLT), pharmacokinetics, pharmacodynamics, and immunogenicity of CAR-GPRC5D in different dose groups. And to preliminarily observe the efficacy in small samples of patients with R/R MM or Plasma cell leukemia and confirm the recommended phase II dose (RP2D).
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CAR-GPRC5D cells<br>The tolerability and safety of CARGPRC5D cells will be assessed according to the 3+3 doseescalation design.There will be three dose levels, 0.5×10^6, 1.0×10^6, 2.0x10^6cells/kg. For each level, 3-6 subjects will be enrolled. | Drug: CAR-T (CAR-GPRC5D)<br>* CAR-GPRC5D is an individualized, gene-modified autologous T cell immunotherapy product targeting GPRC5D that identifies and eliminates malignant and normal cells expressing GPRC5D. CAR specifically recognizes GPRC5D with a hypoimmunogenic human single-chain variable fragment (ScFv) that promotes car-T activation, proliferation and cytokine secretion. The persistence of CAR-T is enhanced by 4-1BB costimulation signal.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of dose-limiting toxicity (DLT) by dose group | Dose limiting toxicity will be assessed after infusion in each dose group | 2 years after CAR-T cell infusion | 
| Type and incidence of adverse events (AEs) and serious adverse events (SAEs) by dose group | Calculate type and incidence of adverse events (AE), serious adverse event (SAE), including those happened after lymphodepletion and after infusion, those related to study drug and lymphodepletion, or those that led to withdrawal from the study. They will also be aggregated by systematic organ classification (SOC), preferred term (PT), and severity | 2 years after CAR-T cell infusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective response rate (ORR) | The percentage of participants who achieved PR or better response. | 2 years after CAR-T cell infusion | 
| Overall survival (OS) | OS is measured from the date of the initial infusion of CAR-GPRC5D to the date of the participant's death | 2 years after CAR-T cell infusion | 
| Duration of response (DOR) after administration | DOR will be calculated among responders (with a PR or better response) from the date of initial documentation of a response (PR or better) to the date of first documented evidence of progressive disease, as defined in the IMWG criteria | 2 years after CAR-T cell infusion | 
| Progression-free survival (PFS) | PFS is measured from the date of the initial infusion of CAR-GPRC5D of participants to the first time of disease progression or death for any reason | 2 years after CAR-T cell infusion | 
| Time to response (TTR) | The time interval between the first treatment of CAR-GPRC5D and the time of first recording of sCR or CR or VGPR or PR of the participants | 2 years after CAR-T cell infusion | 
| Time to complete Response (TTCR) | Time from CAR-GPRC5D infusion to first documentation of complete response of the participants | 2 years after CAR-T cell infusion | 
| Percentage of Participants With Negative Minimal Residual Disease (MRD) | MRD negative rate is defined as the proportion of participants who achieve MRD negative status by the respective time point | 2 years after CAR-T cell infusion | 
| Pharmacokinetics - Cmax | The maximum transgene level at Tmax | 2 years after CAR-T cell infusion | 
| Pharmacokinetics - Tmax | Time to peak transgene level | 2 years after CAR-T cell infusion | 
| Pharmacokinetics - AUC0-28days | Area under the curve of CAR-T cells from time zero to Day 28 | 2 years after CAR-T cell infusion | 
| Pharmacokinetics - AUC0-90days | Area under the curve of CAR T cells from time zero to Day 90 | 2 years after CAR-T cell infusion | 
| PD endpoints - the level of free CAR-GPRC5D | The content of free CAR-GPRC5D in peripheral blood will be detected at each time point | 2 years after CAR-T cell infusion | 
| PD endpoints - the levels of CAR-T-related serum cytokines | The concentration levels of CAR-T-related serum cytokines (such as IL-6) will be detected at each time point | 2 years after CAR-T cell infusion | 
| Health-related quality of life assessment | HRQoL will be assessed by the European Organization for Cancer Research and Treatment Quality of Life Questionnaire (EORTC-QLQ-C30) | 2 years after CAR-T cell infusion | 
| Evaluation of lymphocyte subsets | Lymphocyte subsets will be assessed by FACS | 2 years after CAR-T cell infusion | 
| Levels of immunoglobulins | Immunoglobulins in peripheral blood will be assessed to monitor changes | 2 years after CAR-T cell infusion |