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

January 3, 2025 updated by: Yan Yi, The Third Affiliated Hospital of Southern Medical University
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.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

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 Type

Interventional

Enrollment (Estimated)

60

Phase

  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Locations

  • China
    • Guangdong
      • Guangzhou, Guangdong, China, 510630
        • Recruiting
        • The Third Affiliated Hospital of Southern Medical University
        • Contact:

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Non-Randomized
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Phase 2a: RP2D
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.
Biological: CAR-T
CAR T-cell therapy involves autologous chimeric antigen receptor T-cells, capable of targeting human B cell maturation antigen (BCMA) ,CD19 or CD-7 etc. target molecules of other hematologic malignancies.
Experimental: Phase 1:Low dose group
Infusion of CAR T-cells by single dose of 0.5×10^6 CAR-T cells/kg
Biological: CAR-T
CAR T-cell therapy involves autologous chimeric antigen receptor T-cells, capable of targeting human B cell maturation antigen (BCMA) ,CD19 or CD-7 etc. target molecules of other hematologic malignancies.
Experimental: Phase 1: Medium dose group
Infusion of CAR T-cells by single dose of 1.5×10^6 CAR-T cells/kg
Biological: CAR-T
CAR T-cell therapy involves autologous chimeric antigen receptor T-cells, capable of targeting human B cell maturation antigen (BCMA) ,CD19 or CD-7 etc. target molecules of other hematologic malignancies.
Experimental: Phase 1: High dose group
Infusion of CAR T-cells by single dose of 5.0×10^6 CAR-T cells/kg
Biological: CAR-T
CAR T-cell therapy involves autologous chimeric antigen receptor T-cells, capable of targeting human B cell maturation antigen (BCMA) ,CD19 or CD-7 etc. target molecules of other hematologic malignancies.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Recommended Phase 2 Dose (RP2D)
Time Frame: Through study completion, an average of 1 year
To determine after all subjects in the Phase 1 dose-escalation study completed DLT observation
Through study completion, an average of 1 year
Number of patients with dose-limiting toxicity (DLT)
Time Frame: 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).
Within 30 days of receiving CAR T-cells transfusion therapy
Maximum Tolerated Dose (MTD)
Time Frame: Within 30 days of receiving CAR T-cells transfusion therapy
At least 6 subjects in the MTD dose group must complete the DLT assessment.
Within 30 days of receiving CAR T-cells transfusion therapy
Adverse Event
Time Frame: 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).
Minimum 2 years after CAR T-cells infusion (Day 1)
Objective response rate (ORR)
Time Frame: 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%.
Through study completion, an average of 2 years

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Progression-free Survival (PFS)
Time Frame: 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.
Through study completion, an average of 2 years
Overall Survival (OS)
Time Frame: Through study completion, an average of 2 years
OS is the time from the start of cell infusion to the death of the subject.
Through study completion, an average of 2 years
Stringent complete response rate (sCRR)
Time Frame: 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.
Through study completion, an average of 2 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

The Third Affiliated Hospital of Southern Medical University

Investigators

  • Study Director: Yan Yi, MD.

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Estimated)

January 15, 2025

Primary Completion (Estimated)

December 31, 2028

Study Completion (Estimated)

December 31, 2028

Study Registration Dates

First Submitted

December 27, 2024

First Submitted That Met QC Criteria

January 3, 2025

First Posted (Actual)

March 25, 2025

Study Record Updates

Last Update Posted (Actual)

March 25, 2025

Last Update Submitted That Met QC Criteria

January 3, 2025

Last Verified

July 1, 2024

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 2024-Lunli-020 (Other Identifier: The clinical Trial Ethics Committee)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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