Clinical trial NCT06758713: Safety and Efficacy of Fourth-Generation CAR-T in the Treatment of Hematologic Malignancies
Official title: Safety and Efficacy of Fourth-Generation CAR-T in the Treatment of Hematologic Malignancies
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
Conditions: Multiple Myeloma
B-cell Lymphoma
Hematological Malignancy
Keywords: Multiple myeloma
B-cell lymphoma
Hematological malignancy
CAR-T
Safety
Efficacy
Lead sponsor: The Third Affiliated Hospital of Southern Medical University
Sponsor class: OTHER_GOV
First posted: 2025-01-06
Enrollment: 60
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This is a single center, open-label, dose-escalation/expansion clinical study to evaluate the safety and effectiveness of Fourth-Generation CAR-T, and determine the recommended dose of the CAR T-cells for patients with Multiple Myeloma，B-cell lymphoma and other hematologic malignancies.

Detailed description: This is a single center, open-label, dose-escalation/expansion clinical study to evaluate the safety and efficacy of Fourth-Generation CAR-T in the Treatment of Multiple Myeloma，B-cell lymphoma and other hematologic malignancies.. -Prior to Fourth-Generation CAR-T cells infusion, subjects will receive lymphodepleting therapy with fludarabine and cyclophosphamide. After infusion, the investigators will observe the characteristics of dose limited toxicity (DLT), and determine the maximum tolerable agent MTD and RP2D were confirmed. To provide basis for the dosage and treatment plan of cell products in follow-up clinical trials. Meanwhile, subjects will be followed for side effects and effect of the CAR-T.

Eligibility criteria: Inclusion Criteria:

Subjects must meet all of the following criteria to be enrolled:

1. Voluntarily participate in this clinical study and sign the informed consent form; 2. 18 to 75 years old (including cut-off value), Male and female;; 3. Expected survival of at least 3 months; 4.1 CD19-positive B lymphocyte-derived hematologic malignancies; 4.2 Multiple myeloma patients; 4.3 Non-B cell-derived hematologic malignancies patients with CD7 or other target molecules; 5. The clinical trial values during the screening period meet the following criteria:

1. White blood cell count ≥ 3.0 × 10e9/L; Absolute neutrophil ≥ 1.0 × 10e9/L; Lymphocyte count ≥ 0.5 × 10e9/L. (The growth factor support is allowed, but growth factor must not have been received within 7 days prior to laboratory testing);
2. Platelet count ≥ 50 × 10e9/L (No blood transfusion support within 7 days prior to laboratory tests.); Note: Patients with leukemia, multiple myeloma, and lymphoma are not subject to the above blood picture requirements;
3. Biochemical indicators Serum total bilirubin (TBIL) ≤ 2.5 ULN, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 ULN, or 5 ULN if liver dysfunction is primarily due to tumor invasion); 6. Cardiac function: Subjects must have good hemodynamic stability, left ventricular ejection fraction (LVEF) ≥ 55%; 7. Lung condition: Subjects are not serious infections such as severe pneumonia; 8. ECOG activity status score: 0-2 points; 9. Female subjects must use effective contraception (such as oral prescription contraceptives, injectable contraceptives, intrauterine devices, double blockade, contraceptive patches, male partner sterilization) throughout the study period; Must have a negative serum or urine pregnancy test result at screening and throughout the study.

Exclusion Criteria:

Any one of the following conditions cannot be selected as a subject:

1. Having received CAR-T therapy targeting the same molecule;
2. Having received other immunotargeted therapy targeting the same molecules;
3. Pregnant or lactating women;
4. Subjects who have previously suffered from other malignancies, with the following exceptions:

   1. Having received curative therapy, and no known active disease in the ≥ 3 years prior to the enrollment;
   2. Non melanoma skin cancer subjects who have completed sufficient treatment and no evidence of thecurrent disease;
5. Subjects with a severe mental disorder;
6. Subjects with active autoimmune disease requiring immunotherapy;
7. Having received allogeneic hematopoietic stem cell transplantation;
8. Subjects with significant cardiovascular diseasesa.uncontrolled or symptomatic arrhythmias, congestive heart failure, or any heart disease with cardiac function grade 3 or grade 4 (according to the functional classification method of the New York Heart Association NYHA); b. Myocardial infarction or coronary artery bypass grafting within 6 months prior to screening); c. Clinically significant history of ventricular arrhythmia or unexplained syncope (non vaso-vagal or not due to dehydration);
9. Subjects with active infectious disease including 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, active pulmonary tuberculosis; or with any significant infection requiring high-grade antibiotics Event;
10. Subjects with dysfunction of important organssuch as organ function in the following abnormalities:

    1. Serum AST or ALT \> 2.5×ULN, or \> 5ULN if liver function is predominantly due to tumor invasion; TBIL \> 2.5 × ULN, unless the subject is Gilbert's syndrome;
    2. Serum creatinine\>2.5mg/dl;
    3. Partial prothrombin time or activated partial thromboplastin time or international normalized ratio \> 1.5×ULN in the absence of anticoagulant therapy;
11. Participation in other clinical studies or prior treatment with any gene therapy product in the past three months;
12. Subjects with uncontrolled diabetes mellitus (glycosylated hemoglobin HbAlc \>8% at screening);13. Highly allergic constitution or history of severe allergies, and having contraindications to cyclophosphamide or fludarabine;

14. Feasibility assessment screening demonstrated \<10% transfection of targeted lymphocytes or underamplification under CD3 / CD28 costimulation (\<5-fold); 15. Subjects who are considered unsuitable to participate in this trial by the investigator.

Primary outcomes:
measure: Number of patients with dose-limiting toxicity (DLT)
timeFrame: Within 30 days of receiving CAR T-cells transfusion therapy
measure: Maximum Tolerated Dose (MTD)
timeFrame: Within 30 days of receiving CAR T-cells transfusion therapy
measure: Adverse Event
timeFrame: Minimum 2 years after CAR T-cells infusion (Day 1)
measure: Recommended Phase 2 Dose (RP2D)
timeFrame: Through study completion, an average of 1 year
measure: Objective response rate (ORR)
timeFrame: Through study completion, an average of 2 years
Secondary outcomes:
measure: Stringent complete response rate (sCRR)
timeFrame: Through study completion, an average of 2 years
measure: Progression-free Survival (PFS)
timeFrame: Through study completion, an average of 2 years
measure: Overall Survival (OS)
timeFrame: Through study completion, an average of 2 years
Other outcomes:
Locations:
city: Guangzhou
country: China
facility: The Third Affiliated Hospital of Southern Medical University
state: Guangdong
Study officials:
name: Yan Yi, MD.
role: STUDY_DIRECTOR
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