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

NCT06758713 | Recruiting Phase 1 DMC

• 1 other identifier: 2024-Lunli-020
• Study Type: interventional
• Target: 60
• Locations: 1 country
• Sites: 1

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.

Conditions

Multiple Myeloma; B-cell Lymphoma; Hematological Malignancy

Keywords

Multiple myeloma; B-cell lymphoma; Hematological malignancy; CAR-T; Safety; Efficacy

Outcome Measures

Primary Outcomes (5)

• Number of patients with dose-limiting toxicity (DLT)

  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)

  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

  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)

• Recommended Phase 2 Dose (RP2D)

  To determine after all subjects in the Phase 1 dose-escalation study completed DLT observation

  Through study completion, an average of 1 year

• Objective response rate (ORR)

  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 Outcomes (3)

• Stringent complete response rate (sCRR)

  Through study completion, an average of 2 years

• Progression-free Survival (PFS)

  Through study completion, an average of 2 years

• Overall Survival (OS)

  Through study completion, an average of 2 years

Study Arms (4)

Phase 1:Low dose group

EXPERIMENTAL

Infusion of CAR T-cells by single dose of 0.5×10\^6 CAR-T cells/kg

Biological: CAR-T

Phase 1: Medium dose group

EXPERIMENTAL

Infusion of CAR T-cells by single dose of 1.5×10\^6 CAR-T cells/kg

Biological: CAR-T

Phase 1: High dose group

EXPERIMENTAL

Infusion of CAR T-cells by single dose of 5.0×10\^6 CAR-T cells/kg

Biological: CAR-T

Phase 2a: RP2D

EXPERIMENTAL

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

Interventions

CAR-T BIOLOGICAL

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.

Phase 1: High dose group; Phase 1: Medium dose group; Phase 1:Low dose group; Phase 2a: RP2D

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Subjects must meet all of the following criteria to be enrolled:
• \. 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:
• 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);
• 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;
• 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.

You may not qualify if:

• Any one of the following conditions cannot be selected as a subject:
• Having received CAR-T therapy targeting the same molecule;
• Having received other immunotargeted therapy targeting the same molecules;
• Pregnant or lactating women;
• Subjects who have previously suffered from other malignancies, with the following exceptions:
• Having received curative therapy, and no known active disease in the ≥ 3 years prior to the enrollment;
• Non melanoma skin cancer subjects who have completed sufficient treatment and no evidence of thecurrent disease;
• Subjects with a severe mental disorder;
• Subjects with active autoimmune disease requiring immunotherapy;
• Having received allogeneic hematopoietic stem cell transplantation;
• 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);
• 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;
• Subjects with dysfunction of important organssuch as organ function in the following abnormalities:
• 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;
• Serum creatinine\>2.5mg/dl;

Sponsors & Collaborators

• The Third Affiliated Hospital of Southern Medical University: lead

Study Sites (1)

The Third Affiliated Hospital of Southern Medical University

Guangzhou, Guangdong, 510630, China

RECRUITING

Related Publications (8)

• Roddie C, Dias J, O'Reilly MA, Abbasian M, Cadinanos-Garai A, Vispute K, Bosshard-Carter L, Mitsikakou M, Mehra V, Roddy H, Hartley JA, Spanswick V, Lowe H, Popova B, Clifton-Hadley L, Wheeler G, Olejnik J, Bloor A, Irvine D, Wood L, Marzolini MAV, Domning S, Farzaneh F, Lowdell MW, Linch DC, Pule MA, Peggs KS. Durable Responses and Low Toxicity After Fast Off-Rate CD19 Chimeric Antigen Receptor-T Therapy in Adults With Relapsed or Refractory B-Cell Acute Lymphoblastic Leukemia. J Clin Oncol. 2021 Oct 20;39(30):3352-3363. doi: 10.1200/JCO.21.00917. Epub 2021 Aug 31.

  PMID: 34464155 BACKGROUND

• Sang W, Wang X, Geng H, Li T, Li D, Zhang B, Zhou Y, Song X, Sun C, Yan D, Li D, Li Z, Li C, Xu K. Anti-PD-1 Therapy Enhances the Efficacy of CD30-Directed Chimeric Antigen Receptor T Cell Therapy in Patients With Relapsed/Refractory CD30+ Lymphoma. Front Immunol. 2022 Apr 1;13:858021. doi: 10.3389/fimmu.2022.858021. eCollection 2022.

  PMID: 35432352 BACKGROUND

• Du J, Wei R, Jiang S, Jiang H, Li L, Qiang W, He H, Shi L, Ma Q, Yu K, Zhang X, Ding H, Sun X, Xiang F, Zhu L, Cheng Z, Fu W. CAR-T cell therapy targeting B cell maturation antigen is effective for relapsed/refractory multiple myeloma, including cases with poor performance status. Am J Hematol. 2022 Jul;97(7):933-941. doi: 10.1002/ajh.26583. Epub 2022 May 5.

  PMID: 35488407 BACKGROUND

• Yang J, He J, Zhang X, Li J, Wang Z, Zhang Y, Qiu L, Wu Q, Sun Z, Ye X, Yin W, Cao W, Shen L, Sersch M, Lu P. Next-day manufacture of a novel anti-CD19 CAR-T therapy for B-cell acute lymphoblastic leukemia: first-in-human clinical study. Blood Cancer J. 2022 Jul 7;12(7):104. doi: 10.1038/s41408-022-00694-6.

  PMID: 35798714 BACKGROUND

• Qu C, Zou R, Wang P, Zhu Q, Kang L, Ping N, Xia F, Liu H, Kong D, Yu L, Wu D, Jin Z. Decitabine-primed tandem CD19/CD22 CAR-T therapy in relapsed/refractory diffuse large B-cell lymphoma patients. Front Immunol. 2022 Aug 17;13:969660. doi: 10.3389/fimmu.2022.969660. eCollection 2022.

  PMID: 36059523 BACKGROUND

• Ying Z, Xie Y, Zheng W, Liu W, Lin N, Tu M, Wang X, Ping L, Deng L, Zhang C, Wu M, Feng F, Du T, Tang Y, Su F, Guo Z, Li J, Song Y, Zhu J. Efficacy and safety of relmacabtagene autoleucel, an anti-CD19 chimeric antigen receptor T cell, in relapsed/refractory B-cell non-Hodgkin's lymphoma: 2-year results of a phase 1 trial. Bone Marrow Transplant. 2023 Mar;58(3):288-294. doi: 10.1038/s41409-022-01888-z. Epub 2022 Dec 7.

  PMID: 36477110 BACKGROUND

• Liang EC, Albittar A, Huang JJ, Hirayama AV, Kimble EL, Portuguese AJ, Chapuis A, Shadman M, Till BG, Cassaday RD, Milano F, Kiem HP, Riddell SR, Turtle CJ, Maloney DG, Gauthier J. Factors associated with long-term outcomes of CD19 CAR T-cell therapy for relapsed/refractory CLL. Blood Adv. 2023 Nov 28;7(22):6990-7005. doi: 10.1182/bloodadvances.2023011399.

  PMID: 37774014 BACKGROUND

• Minson A, Hamad N, Cheah CY, Tam C, Blombery P, Westerman D, Ritchie D, Morgan H, Holzwart N, Lade S, Anderson MA, Khot A, Seymour JF, Robertson M, Caldwell I, Ryland G, Saghebi J, Sabahi Z, Xie J, Koldej R, Dickinson M. CAR T cells and time-limited ibrutinib as treatment for relapsed/refractory mantle cell lymphoma: the phase 2 TARMAC study. Blood. 2024 Feb 22;143(8):673-684. doi: 10.1182/blood.2023021306.

  PMID: 37883795 BACKGROUND

MeSH Terms

Conditions

Multiple Myeloma; Lymphoma, B-Cell; Hematologic Neoplasms

Condition Hierarchy (Ancestors)

Neoplasms, Plasma Cell; Neoplasms by Histologic Type; Neoplasms; Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Paraproteinemias; Blood Protein Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Hemorrhagic Disorders; Lymphoproliferative Disorders; Immunoproliferative Disorders; Immune System Diseases; Lymphoma, Non-Hodgkin; Lymphoma; Lymphatic Diseases; Neoplasms by Site

Study Officials

• Yan Yi, MD.

  STUDY DIRECTOR

Central Study Contacts

Yan Yi, MD.

CONTACT

+86 13617493781; yiyan@smu.edu.cn

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER GOV
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: MD.

Study Record Dates

• First Submitted: December 27, 2024
• First Posted: January 6, 2025
• Study Start: January 15, 2025
• Primary Completion (Estimated): December 31, 2028
• Study Completion (Estimated): December 31, 2028
• Last Updated: January 6, 2025

Record last verified: 2024-07

Data Sharing

• IPD Sharing: Will not share

Locations

CN (1)