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

Primary Purpose

Relapsed/Refractory Multiple Myeloma, Plasma Cell Leukemia

Status
Recruiting
Phase
Phase 1
Locations
China
Study Type
Interventional
Intervention
CAR-T (CAR-GPRC5D)
Sponsored by
Chunrui Li
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Relapsed/Refractory Multiple Myeloma focused on measuring CAR-T, GPRC5D

Eligibility Criteria

18 Years - 75 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Subjects must satisfy all the following criteria to be enrolled in the study:

    1. age 18 to 75 years old, male or female.
    2. 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;

    3. 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).
    4. 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 ≥ 0.5 g/dL. 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

    5. ECOG performance score 0-2.
    6. Estimated life expectancy ≥ 12 weeks.
    7. 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%.
    8. 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.
    9. 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:

    1. Subjects who are known to have GVHD or need long-term immunosuppressive therapy.
    2. 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.

    3. 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.
    4. Subjects with hypertension that cannot be controlled by medication.
    5. 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.
    6. 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.
    7. 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.
    8. Subjects with a history of organ transplantation.
    9. 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).
    10. Subjects participated in another interventional clinical study 1 months before signing the informed consent (ICF);
    11. 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).
    12. 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
    13. Pregnant or lactating women.
    14. Subjects with mental illness or consciousness disorder or disease of the central nervous system
    15. Other conditions that researchers consider inappropriate for inclusion.

Sites / Locations

  • Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

CAR-GPRC5D cells

Arm Description

The tolerability and safety of CAR-GPRC5D cells will be assessed according to the "3+3" dose-escalation design. There will be three dose levels, 0.5×10^6, 1.0×10^6, and 2.0×10^6, CAR+T cells/kg. For each level, 3-6 subjects will be enrolled.

Outcomes

Primary Outcome Measures

Incidence of dose-limiting toxicity (DLT) by dose group
Dose limiting toxicity will be assessed after infusion in each dose group
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

Secondary Outcome Measures

Objective response rate (ORR)
The percentage of participants who achieved PR or better response.
Overall survival (OS)
OS is measured from the date of the initial infusion of CAR-GPRC5D to the date of the participant's death
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
Progression-free survival (PFS)
The time from the start of CAR-GPRC5D treatment for the participants to the first time of disease progression or death for any reason
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
Time to complete Response (TTCR)
Time from CAR-GPRC5D infusion to first documentation of complete response of the participants
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
Pharmacokinetics - Cmax
The maximum transgene level at Tmax
Pharmacokinetics - Tmax
Time to peak transgene level
Pharmacokinetics - AUC0-28days
Area under the curve of CAR-T cells from time zero to Day 28
Pharmacokinetics - AUC0-90days
Area under the curve of CAR T cells from time zero to Day 90
PD endpoints - the level of free CAR-GPRC5D
The content of free CAR-GPRC5D in peripheral blood will be detected at each time point
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
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)
Evaluation of lymphocyte subsets
Lymphocyte subsets will be assessed by FACS
Levels of immunoglobulins
Immunoglobulins in peripheral blood will be assessed to monitor changes

Full Information

First Posted
January 4, 2022
Last Updated
May 17, 2022
Sponsor
Chunrui Li
Collaborators
Nanjing IASO Biotechnology Co., Ltd.
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1. Study Identification

Unique Protocol Identification Number
NCT05219721
Brief Title
A Study of CAR-GPRC5D in Patients With Relapsed/Refractory Multiple Myeloma or Plasma Cell Leukemia
Official Title
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
Study Type
Interventional

2. Study Status

Record Verification Date
May 2022
Overall Recruitment Status
Recruiting
Study Start Date
March 17, 2022 (Actual)
Primary Completion Date
December 31, 2022 (Anticipated)
Study Completion Date
March 1, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Chunrui Li
Collaborators
Nanjing IASO Biotechnology Co., Ltd.

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
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
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Relapsed/Refractory Multiple Myeloma, Plasma Cell Leukemia
Keywords
CAR-T, GPRC5D

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
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)
Allocation
N/A
Enrollment
18 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
CAR-GPRC5D cells
Arm Type
Experimental
Arm Description
The tolerability and safety of CAR-GPRC5D cells will be assessed according to the "3+3" dose-escalation design. There will be three dose levels, 0.5×10^6, 1.0×10^6, and 2.0×10^6, CAR+T cells/kg. For each level, 3-6 subjects will be enrolled.
Intervention Type
Drug
Intervention Name(s)
CAR-T (CAR-GPRC5D)
Intervention Description
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, cytokine secretion and target cell killing through the CD3ζ domain. The amplification and persistence of CAR T are enhanced by 4-1BB costimulation signal.
Primary Outcome Measure Information:
Title
Incidence of dose-limiting toxicity (DLT) by dose group
Description
Dose limiting toxicity will be assessed after infusion in each dose group
Time Frame
2 years after CAR-T cell infusion
Title
Type and incidence of adverse events (AEs) and serious adverse events (SAEs) by dose group
Description
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
Time Frame
2 years after CAR-T cell infusion
Secondary Outcome Measure Information:
Title
Objective response rate (ORR)
Description
The percentage of participants who achieved PR or better response.
Time Frame
2 years after CAR-T cell infusion
Title
Overall survival (OS)
Description
OS is measured from the date of the initial infusion of CAR-GPRC5D to the date of the participant's death
Time Frame
2 years after CAR-T cell infusion
Title
Duration of response (DOR) after administration
Description
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
Time Frame
2 years after CAR-T cell infusion
Title
Progression-free survival (PFS)
Description
The time from the start of CAR-GPRC5D treatment for the participants to the first time of disease progression or death for any reason
Time Frame
2 years after CAR-T cell infusion
Title
Time to response (TTR)
Description
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
Time Frame
2 years after CAR-T cell infusion
Title
Time to complete Response (TTCR)
Description
Time from CAR-GPRC5D infusion to first documentation of complete response of the participants
Time Frame
2 years after CAR-T cell infusion
Title
Percentage of Participants With Negative Minimal Residual Disease (MRD)
Description
MRD negative rate is defined as the proportion of participants who achieve MRD negative status by the respective time point
Time Frame
2 years after CAR-T cell infusion
Title
Pharmacokinetics - Cmax
Description
The maximum transgene level at Tmax
Time Frame
2 years after CAR-T cell infusion
Title
Pharmacokinetics - Tmax
Description
Time to peak transgene level
Time Frame
2 years after CAR-T cell infusion
Title
Pharmacokinetics - AUC0-28days
Description
Area under the curve of CAR-T cells from time zero to Day 28
Time Frame
2 years after CAR-T cell infusion
Title
Pharmacokinetics - AUC0-90days
Description
Area under the curve of CAR T cells from time zero to Day 90
Time Frame
2 years after CAR-T cell infusion
Title
PD endpoints - the level of free CAR-GPRC5D
Description
The content of free CAR-GPRC5D in peripheral blood will be detected at each time point
Time Frame
2 years after CAR-T cell infusion
Title
PD endpoints - the levels of CAR-T-related serum cytokines
Description
The concentration levels of CAR-T-related serum cytokines (such as IL-6) will be detected at each time point
Time Frame
2 years after CAR-T cell infusion
Title
Health-related quality of life assessment
Description
HRQoL will be assessed by the European Organization for Cancer Research and Treatment Quality of Life Questionnaire (EORTC-QLQ-C30)
Time Frame
2 years after CAR-T cell infusion
Title
Evaluation of lymphocyte subsets
Description
Lymphocyte subsets will be assessed by FACS
Time Frame
2 years after CAR-T cell infusion
Title
Levels of immunoglobulins
Description
Immunoglobulins in peripheral blood will be assessed to monitor changes
Time Frame
2 years after CAR-T cell infusion
Other Pre-specified Outcome Measures:
Title
Positive rate of human anti-CAR antibody
Description
The levels of human anti-CAR antibody of participants will be detected
Time Frame
2 years after CAR-T cell infusion
Title
Number of Participants with replication competent lentivirus (RCL)
Description
Number of participants exhibiting anti-drug antibodies for CAR-GPRC5D will be reported
Time Frame
2 years after CAR-T cell infusion

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
75 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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 ≥ 0.5 g/dL. 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.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Chunrui Li
Phone
86-13647233185
Email
cunrui5650@126.com
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Chunrui Li
Organizational Affiliation
Tongji Hospital affiliated to Tongji Medical College of Huazhong University of Science & Technology
Official's Role
Principal Investigator
Facility Information:
Facility Name
Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology
City
Wuhan
State/Province
Hu Bei
ZIP/Postal Code
430000
Country
China
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Chunrui Li
Phone
+86 13647233185
Email
cunrui5650@126.com

12. IPD Sharing Statement

Learn more about this trial

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

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