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

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

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.

Study Overview

• Status: Recruiting
• Conditions: Plasma Cell Leukemia; Relapsed/Refractory Multiple Myeloma
• Intervention / Treatment: Drug: CAR-T (CAR-GPRC5D)

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.

• Study Type: Interventional
• Enrollment (Anticipated): 18
• Phase: Phase 1

Contacts and Locations

Study Locations

• China
  • Hu Bei
    • Wuhan, Hu Bei, China, 430000
      • Recruiting
      • Tongji hospital, Tongji Medical College, Huazhong University of Science and Technology

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: CAR-GPRC5D cells; 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.

Drug: CAR-T (CAR-GPRC5D); 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.

What is the study measuring?

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)	The time from the start of CAR-GPRC5D treatment for the 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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Positive rate of human anti-CAR antibody	The levels of human anti-CAR antibody of participants will be detected	2 years after CAR-T cell infusion
Number of Participants with replication competent lentivirus (RCL)	Number of participants exhibiting anti-drug antibodies for CAR-GPRC5D will be reported	2 years after CAR-T cell infusion

Collaborators and Investigators

• Sponsor: Chunrui Li
• Collaborators: Nanjing IASO Biotechnology Co., Ltd

Study record dates

Study Major Dates

• Study Start (Actual): March 17, 2022
• Primary Completion (Anticipated): December 31, 2022
• Study Completion (Anticipated): March 1, 2024

Study Registration Dates

• First Submitted: January 4, 2022
• First Submitted That Met QC Criteria: January 20, 2022
• First Posted (Actual): February 2, 2022

Study Record Updates

• Last Update Posted (Actual): May 24, 2022
• Last Update Submitted That Met QC Criteria: May 17, 2022
• Last Verified: May 1, 2022

More Information

Terms related to this study

• Keywords: CAR-T; GPRC5D
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Immunoproliferative Disorders; Hematologic Diseases; Hemorrhagic Disorders; Hemostatic Disorders; Paraproteinemias; Blood Protein Disorders; Multiple Myeloma; Neoplasms, Plasma Cell; Leukemia; Leukemia, Plasma Cell
• Other Study ID Numbers: CAR-GPRC5DCI001

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No