Safety and Efficacy of Fourth-Generation CAR-T in the Treatment of Hematologic Malignancies

Phase 1

Recruiting

• Conditions: Multiple Myeloma; B-cell Lymphoma; Hematological Malignancy
• Interventions: Biological: CAR-T

• Registration Number: NCT06758713
• Lead Sponsor: The Third Affiliated Hospital of Southern Medical University

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.

Study Timeline

• Status Verified: 2024-07
• Study First Submitted: 2024-12-27
• Study First Submitted QC: 2025-01-03
• Last Update Submitted: 2025-01-03
• Study First Posted: 2025-01-06
• Last Update Posted: 2025-01-06
• Study Start: 2025-01-15
• Primary Completion: 2028-12-31
• Study Completion: 2028-12-31

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 60

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:

2. 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);

3. 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;

4. 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;

13. 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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Phase 1:Low dose group	CAR-T	Infusion of CAR T-cells by single dose of 0.5×10\^6 CAR-T cells/kg
Phase 1: Medium dose group	CAR-T	Infusion of CAR T-cells by single dose of 1.5×10\^6 CAR-T cells/kg
Phase 1: High dose group	CAR-T	Infusion of CAR T-cells by single dose of 5.0×10\^6 CAR-T cells/kg
Phase 2a: RP2D	CAR-T	After all subjects in the Phase 1 dose-escalation study completed DLT observation, RP2D was determined based on the analysis results for the phase 2a expansion study.

Primary Outcome Measures

Name	Time	Method
Number of patients with dose-limiting toxicity (DLT)	Within 30 days of receiving CAR T-cells transfusion therapy	For DLT evaluation, severity (grade) is classified according to common terminology criteria for adverse events version 4.03 (CTCAE v4.03).
Maximum Tolerated Dose (MTD)	Within 30 days of receiving CAR T-cells transfusion therapy	At least 6 subjects in the MTD dose group must complete the DLT assessment.
Adverse Event	Minimum 2 years after CAR T-cells infusion (Day 1)	Safety will be assessed by adverse events (AEs), which include clinically significant abnormalities identified during medical tests (e.g. laboratory tests, electrocardiogram, imaging examinations or physical examinations). AEs will be coded by Medical Dictionary for Regulatory Activities (MeDRA) and their severity will be graded according to the NCI Common Terminology Criteria for Adverse Events (CTCAE, version 4.03).
Recommended Phase 2 Dose (RP2D)	Through study completion, an average of 1 year	To determine after all subjects in the Phase 1 dose-escalation study completed DLT observation
Objective response rate (ORR)	Through study completion, an average of 2 years	The definition of ORR is the proportion of subjects achieving sCR, CR, VGPR, or PR confirmed by efficacy reassessment after a minimum interval of three months. ORR is calculated as (sCR+CR+VGPR+PR) divided by the total number of cases of Multiple Myeloma, or (CR+PR) divided by the total number of cases of B-cell lymphoma and other hematologic malignancies, multiplied by 100%.

Secondary Outcome Measures

Name	Time	Method
Progression-free Survival (PFS)	Through study completion, an average of 2 years	The time interval from the first administration of the investigational drug to the first observation of disease progression is calculated, considering the date of entry for patients who died for reasons other than disease progression before progression occurred.
Overall Survival (OS)	Through study completion, an average of 2 years	OS is the time from the start of cell infusion to the death of the subject.
Stringent complete response rate (sCRR)	Through study completion, an average of 2 years	The definition of sCRR is the proportion of subjects achieving sCR confirmed by efficacy re-assessment after a minimum interval of three months. Efficacy assessment for multiple myeloma only.

Trial Locations

Locations (1)

The Third Affiliated Hospital of Southern Medical University; 🇨🇳 Guangzhou, Guangdong, China