Clinical trial NCT05759793: 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
Overall status: RECRUITING
Phase: PHASE1
Conditions: Relapsed/Refractory Multiple Myeloma
Plasma Cell Leukemia
Keywords: GPRC5D
RRMM
PCL
Lead sponsor: Nanjing IASO Biotechnology Co., Ltd.
Sponsor class: INDUSTRY
Collaborators: name: Ruijin Hospital
First posted: 2023-03-08
Enrollment: 12
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: This study pre-defined three dose levels of 1.0×10\^6 CAR-T/Kg, 2.0×10\^6 CAR-T/Kg, 3.0×10\^6 CAR-T/Kg. Each dose level will enroll 3-6 subjects, and the estimated total number of subjects will be 9-18. 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).
Primary purpose: TREATMENT

Brief summary: This study is a single-center, open-label, 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: Apheresis will be performed to manufacture CAR-GPRC5D CAR-T cells. Bridging therapy is allowed between apheresis and lymphodepletion. Lymphodepletion with fludarabine and cyclophosphamide was performed for three consecutive days. Then, subjects will receive a single dose infusion of CAR-GPRC5D at 1.0, 2.0, or 3.0 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.

Eligibility criteria: 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:

   1. The proportion of primitive immature or monoclonal plasma cells detected by bone marrow cytology, bone marrow biopsy, or flow cytometry is ≥ 10%.
   2. Serum M-protein ≥ 10 g/L for IgG type, serum M-protein ≥ 5 g/L for other types, such as IgA, IgD, IgM, IgE.
   3. Urine M-protein ≥ 200 mg/24 hrs.
   4. 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.
   5. 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:

   1. 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).
   2. Liver function: Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5×upper limit of normal (ULN); total serum bilirubin ≤ 1.5×ULN.
   3. Renal function: Creatinine clearance rate (CrCl) calculated according to Cockcroft-Gault formula ≥ 40 ml/min.
   4. Coagulation function: Fibrinogen ≥ 1.0 g/L; activated partial thromboplastin time (APTT) ≤ 1.5×ULN, prothrombin time (PT) ≤1.5×ULN.
   5. SpO2 \> 91%.
   6. 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.

Primary outcomes:
measure: Incidence of dose-limiting toxicity (DLT) by dose group
timeFrame: 28 days after CAR-T cell infusion
measure: Type and incidence of adverse events (AEs) and serious adverse events (SAEs) by dose group
timeFrame: 2 years after CAR-T cell infusion
Secondary outcomes:
measure: Objective response rate (ORR)
timeFrame: 2 years after CAR-T cell infusion
measure: Overall survival (OS)
timeFrame: 2 years after CAR-T cell infusion
measure: Duration of response (DOR) after administration
timeFrame: 2 years after CAR-T cell infusion
measure: Progression-free survival (PFS)
timeFrame: 2 years after CAR-T cell infusion
measure: Time to response (TTR)
timeFrame: 2 years after CAR-T cell infusion
measure: Time to complete Response (TTCR)
timeFrame: 2 years after CAR-T cell infusion
measure: Percentage of Participants With Negative Minimal Residual Disease (MRD)
timeFrame: 2 years after CAR-T cell infusion
measure: Pharmacokinetics - Cmax
timeFrame: 2 years after CAR-T cell infusion
measure: Pharmacokinetics - Tmax
timeFrame: 2 years after CAR-T cell infusion
measure: Pharmacokinetics - AUC0-28days
timeFrame: 2 years after CAR-T cell infusion
measure: Pharmacokinetics - AUC0-90days
timeFrame: 2 years after CAR-T cell infusion
measure: PD endpoints - the level of free CAR-GPRC5D
timeFrame: 2 years after CAR-T cell infusion
measure: PD endpoints - the levels of CAR-T-related serum cytokines
timeFrame: 2 years after CAR-T cell infusion
measure: Health-related quality of life assessment
timeFrame: 2 years after CAR-T cell infusion
measure: Evaluation of lymphocyte subsets
timeFrame: 2 years after CAR-T cell infusion
measure: Levels of immunoglobulins
timeFrame: 2 years after CAR-T cell infusion
Other outcomes:
measure: Positive rate of human anti-CAR antibody
timeFrame: 2 years after CAR-T cell infusion
measure: Number of Participants with replication competent lentivirus (RCL)
timeFrame: 2 years after CAR-T cell infusion
Locations:
city: Shanghai
country: China
facility: Ruijin Hospital Affiliated with Shanghai Jiao Tong University School of Medicine
Study officials:
References: