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出境医 / 临床实验 / ET019003-T Cells in Relapsed/Refractory CD19+ B-Cell Leukemia and Lymphoma

ET019003-T Cells in Relapsed/Refractory CD19+ B-Cell Leukemia and Lymphoma

Study Description
Brief Summary:
This is a single center, open-label, 3+3 dose escalation, phase 1 study to evaluate the efficacy and safety of ET019003-T cells therapy for patients with relapsed/refractory CD19+ acute lymphoblastic leukemia and lymphoma.

Condition or disease Intervention/treatment Phase
Leukemia Lymphoma Drug: ET019003-T Cells Phase 1

Detailed Description:

ET019003-T cells is a human anti-CD19 CAR-T cells by fusing the anti-CD19 antibody Fab domain with the transmembrane and intracellular domains from the γδTCR, which can avoid mispairing with the T cell's endogenous αβTCR chains. Meanwhile, an independent ET190L1-CSR(Chimeric Signaling Receptor) is added to ET019003-T cells in trans, which can bind CD19 to activate a novel costimulatory domain to further promote T cell proliferation and persistence.

The trial is conducted to explore the safety and efficacy of ET019003-T cells in CD19+ Leukemia and Lymphoma.

Study Design
Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 18 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Intervention Model Description: This study was a single-center, open-label, single-arm, non-randomized,3+3 dose escalation clinical trial.18 patients are separated into 9 leukemia and 9 lymphoma. Each disease has 3 groups by infusion dose level. Each dose group has 3 patients.If no DLT emerges in the group, then the next group uses the subsequent higher dose. If DLT emerges in a single subject in any dose level, 3 more subjects will be enrolled to the same dose level.The maximum dose could be extended.
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Safety and Efficiency Study of ET019003-T Cells in Relapsed/Refractory CD19+ B-Cell Leukemia and Lymphoma
Actual Study Start Date : June 12, 2019
Estimated Primary Completion Date : July 1, 2021
Estimated Study Completion Date : July 1, 2022
Arms and Interventions
Arm Intervention/treatment
Experimental: ET019003-T Cells
The trial will enroll 9 patients with leukemia and 9 patients with lymphoma. Each disease has 3 dose-levels.
 Drug: ET019003-T Cells
Fludarabine 25 mg/day on day -5, -4 and -3; Cyclophosphamide 250 or 300 mg/day on day -5, -4 and -3; ET019003-T Cells on day 0.
Outcome Measures
Primary Outcome Measures :
  1. Incidence of Treatment-related Adverse Events [ Time Frame: 3 years ]
    Therapy-related adverse events will be recorded and assessed according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE, Version 4.0).


Secondary Outcome Measures :
  1. Overall Remission Rate(ORR) of ET019003-T cells in Leukemia and Lymphoma [ Time Frame: 3 years ]
    ORR will be assessed from the first CAR-T cell infusion to death or last follow-up (censored).

  2. Overall survival(OS) of ET019003-T cells in Leukemia and Lymphoma [ Time Frame: 3 years ]
    OS will be assessed from the first CAR-T cell infusion to death or last follow-up (censored).

  3. Progress-free survival(PFS) of ET019003-T cells in Leukemia and Lymphoma [ Time Frame: 3 years ]
    PFS will be assessed from the first CAR-T cell infusion to death or last follow-up (censored).

  4. duration of Response(DOR) of ET019003-T cells in Leukemia and Lymphoma [ Time Frame: 3 years ]
    DOR will be assessed from the first CAR-T cell infusion to death or last follow-up (censored).

  5. Rate of ET019003-T cells in bone marrow cells and peripheral blood cells [ Time Frame: 3 years ]
    In vivo (bone marrow and peripheral blood) rate of ET019003-T cells were determined by means of flow cytometry.

  6. Quantity of ET019003-T CAR copies in bone marrow cells and peripheral blood cells [ Time Frame: 3 years ]
    In vivo (bone marrow and peripheral blood) quantity of ET019003-T CAR copies copies were determined by means of qPCR.


Eligibility Criteria
Layout table for eligibility information
Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Patient or his or her legal guardian voluntarily participates in and signs an informed consent form.
  2. Male or female, aged 18 to 75 years (including 18 and 75 years old).

  3. Pathological and histological examination confirmed CD19+ B-cell malignancies, and patients met the following criteria for refractory or relapsed B-cell malignancies.

    A. Refractory/relapsed B-cell lymphoblastic leukemia (Meeting one of the following) i. Recurrence within 6 months after first remission. ii. Primary refractory disease which cannot achieve complete remission (CR) after 2 cycles of standardized chemotherapy regimen.

    iii. Failure to achieve CR or relapse after one line or multiple lines of salvage chemotherapy.

    iv. Not suitable for hematopoietic stem cell transplantation (HSCT), or abandon HSCT due to various restrictions, or relapse after HSCT.

    B. Refractory/relapsed B-cell lymphoma (Meeting 1 of the first 4 items plus item 5) i. Tumor shrinkage less than 50% or disease progression after 4 cycles of standard chemotherapy.

    ii. Achieved CR after standard chemotherapy, but relapsed within 6 months. iii. Two or more relapses after CR. iv. Not suitable for HSCT, or abandon HSCT due to various restrictions, or relapse after HSCT.

    v. Subjects must have received adequate treatment in the past, including anti-CD20 monoclonal antibody and combination chemotherapy with anthracyclines.

  4. Having a measurable or evaluable lesion:

    A. Patients with lymphoma require a single lesion≥15mm or 2 or more lesions≥10mm.

    B. Patients with leukemia require persistent positive or positive relapse of bone marrow MRD.

  5. Patient's main organs functioning well:

    A. Liver function: ALT/AST < 3 times the upper limit of normal (ULN) and total bilirubin≤34.2μmol/L.

    B. Renal function: Creatinine < 220μmol/L. C. Pulmonary function: Indoor oxygen saturation≥95%. D. Cardiac Function: Left ventricular ejection fraction (LVEF) ≥40%.

  6. Patients did not receive any antitumor treatments such as chemotherapy, radiotherapy and immunotherapy within 4 weeks before enrollment, and the toxicity related to previous treatments had returned to < 1 level at enrollment (except for low grade toxicity such as alopecia).
  7. Patients' peripheral superficial venous blood flow smoothly, which can meet the needs of intravenous drip.
  8. ECOG score≤ 2, estimated survival time≥3 months.

Exclusion Criteria:

  1. Women who are pregnant or breastfeeding.
  2. Women of child-bearing potential and all male participants can't use effective methods of contraception for at least 12 months following infusion.
  3. Patients fail to collect enough PBMC.
  4. Patients with other uncontrolled diseases, such as active infections.
  5. Active replication of hepatitis B or active hepatitis C.
  6. Known HIV positive patients.
  7. Patients with active autoimmune diseases requiring systemic immunosuppressive therapy.
  8. Participants with other active malignancies (except non-melanoma skin cancer and cervical cancer) within three years. Patients with a history of successfully-treated tumors with no sign of recurrence in the last two years may be enrolled.
  9. Patients with severe mental disorder or disorders of consciousness.

  10. Organ failure:

    A. Heart: Patients with NYHA class III or higher cardiac failure, or with malignant arrhythmia.

    B. Liver: Patients with Wuhan Conference Classification (1983) class III or higher liver failure.

    C. Kidney: patients with 3rd stage and above kidney failure.

  11. Patients use glucocorticoid or another immune inhibitor in two weeks.
  12. Patients with insufficient T cells or T cell transfection problem.
  13. Patients who need immediate treatment to control tumor progression or relieve tumor burden.
  14. Patients took other clinical treatments within 6 weeks.
  15. Patients with drug addiction.
  16. Patients with poor treatment compliance or difficult to communicate and other problems.
Contacts and Locations

Contacts
Layout table for location contacts
Contact: Yu Hu, M.D., Ph.D 86 13986183871 dr_huyu@126.com
Contact: Heng Mei, M.D., Ph.D 86 13886160811 hmei@hust.edu.cn

Locations
Layout table for location information
China, Hubei
Union Hospital, Tongji Medical College, Huazhong University of Science and Technology Recruiting
Wuhan, Hubei, China, 430022
Contact: Yu Hu, MD., PH.D    86-13986183871    dr_huyu@126.com   
Contact: Heng Mei, MD., PH.D    86-13886160811    hmei@hust.edu.cn   
Sponsors and Collaborators
Wuhan Union Hospital, China
Eureka(Beijing) Biotechnology Co., Ltd.
Investigators
Layout table for investigator information
Principal Investigator: Heng Mei, M.D., Ph.D Wuhan Union Hospital, China
Tracking Information
First Submitted Date  ICMJE July 2, 2019
First Posted Date  ICMJE July 10, 2019
Last Update Posted Date April 8, 2021
Actual Study Start Date  ICMJE June 12, 2019
Estimated Primary Completion Date July 1, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 8, 2019) 		Incidence of Treatment-related Adverse Events [ Time Frame: 3 years ]
Therapy-related adverse events will be recorded and assessed according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE, Version 4.0).
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: July 8, 2019)
  • Overall Remission Rate(ORR) of ET019003-T cells in Leukemia and Lymphoma [ Time Frame: 3 years ]
    ORR will be assessed from the first CAR-T cell infusion to death or last follow-up (censored).
  • Overall survival(OS) of ET019003-T cells in Leukemia and Lymphoma [ Time Frame: 3 years ]
    OS will be assessed from the first CAR-T cell infusion to death or last follow-up (censored).
  • Progress-free survival(PFS) of ET019003-T cells in Leukemia and Lymphoma [ Time Frame: 3 years ]
    PFS will be assessed from the first CAR-T cell infusion to death or last follow-up (censored).
  • duration of Response(DOR) of ET019003-T cells in Leukemia and Lymphoma [ Time Frame: 3 years ]
    DOR will be assessed from the first CAR-T cell infusion to death or last follow-up (censored).
  • Rate of ET019003-T cells in bone marrow cells and peripheral blood cells [ Time Frame: 3 years ]
    In vivo (bone marrow and peripheral blood) rate of ET019003-T cells were determined by means of flow cytometry.
  • Quantity of ET019003-T CAR copies in bone marrow cells and peripheral blood cells [ Time Frame: 3 years ]
    In vivo (bone marrow and peripheral blood) quantity of ET019003-T CAR copies copies were determined by means of qPCR.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE ET019003-T Cells in Relapsed/Refractory CD19+ B-Cell Leukemia and Lymphoma
Official Title  ICMJE Safety and Efficiency Study of ET019003-T Cells in Relapsed/Refractory CD19+ B-Cell Leukemia and Lymphoma
Brief Summary This is a single center, open-label, 3+3 dose escalation, phase 1 study to evaluate the efficacy and safety of ET019003-T cells therapy for patients with relapsed/refractory CD19+ acute lymphoblastic leukemia and lymphoma.
Detailed Description

ET019003-T cells is a human anti-CD19 CAR-T cells by fusing the anti-CD19 antibody Fab domain with the transmembrane and intracellular domains from the γδTCR, which can avoid mispairing with the T cell's endogenous αβTCR chains. Meanwhile, an independent ET190L1-CSR(Chimeric Signaling Receptor) is added to ET019003-T cells in trans, which can bind CD19 to activate a novel costimulatory domain to further promote T cell proliferation and persistence.

The trial is conducted to explore the safety and efficacy of ET019003-T cells in CD19+ Leukemia and Lymphoma.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Intervention Model Description:
This study was a single-center, open-label, single-arm, non-randomized,3+3 dose escalation clinical trial.18 patients are separated into 9 leukemia and 9 lymphoma. Each disease has 3 groups by infusion dose level. Each dose group has 3 patients.If no DLT emerges in the group, then the next group uses the subsequent higher dose. If DLT emerges in a single subject in any dose level, 3 more subjects will be enrolled to the same dose level.The maximum dose could be extended.
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Leukemia
  • Lymphoma
Intervention  ICMJE Drug: ET019003-T Cells
Fludarabine 25 mg/day on day -5, -4 and -3; Cyclophosphamide 250 or 300 mg/day on day -5, -4 and -3; ET019003-T Cells on day 0.
Study Arms  ICMJE Experimental: ET019003-T Cells
The trial will enroll 9 patients with leukemia and 9 patients with lymphoma. Each disease has 3 dose-levels.
Intervention: Drug: ET019003-T Cells
Publications *
  • Schuster SJ, Bishop MR, Tam CS, Waller EK, Borchmann P, McGuirk JP, Jäger U, Jaglowski S, Andreadis C, Westin JR, Fleury I, Bachanova V, Foley SR, Ho PJ, Mielke S, Magenau JM, Holte H, Pantano S, Pacaud LB, Awasthi R, Chu J, Anak Ö, Salles G, Maziarz RT; JULIET Investigators. Tisagenlecleucel in Adult Relapsed or Refractory Diffuse Large B-Cell Lymphoma. N Engl J Med. 2019 Jan 3;380(1):45-56. doi: 10.1056/NEJMoa1804980. Epub 2018 Dec 1.
  • Maude SL, Laetsch TW, Buechner J, Rives S, Boyer M, Bittencourt H, Bader P, Verneris MR, Stefanski HE, Myers GD, Qayed M, De Moerloose B, Hiramatsu H, Schlis K, Davis KL, Martin PL, Nemecek ER, Yanik GA, Peters C, Baruchel A, Boissel N, Mechinaud F, Balduzzi A, Krueger J, June CH, Levine BL, Wood P, Taran T, Leung M, Mueller KT, Zhang Y, Sen K, Lebwohl D, Pulsipher MA, Grupp SA. Tisagenlecleucel in Children and Young Adults with B-Cell Lymphoblastic Leukemia. N Engl J Med. 2018 Feb 1;378(5):439-448. doi: 10.1056/NEJMoa1709866.
  • Neelapu SS, Locke FL, Bartlett NL, Lekakis LJ, Miklos DB, Jacobson CA, Braunschweig I, Oluwole OO, Siddiqi T, Lin Y, Timmerman JM, Stiff PJ, Friedberg JW, Flinn IW, Goy A, Hill BT, Smith MR, Deol A, Farooq U, McSweeney P, Munoz J, Avivi I, Castro JE, Westin JR, Chavez JC, Ghobadi A, Komanduri KV, Levy R, Jacobsen ED, Witzig TE, Reagan P, Bot A, Rossi J, Navale L, Jiang Y, Aycock J, Elias M, Chang D, Wiezorek J, Go WY. Axicabtagene Ciloleucel CAR T-Cell Therapy in Refractory Large B-Cell Lymphoma. N Engl J Med. 2017 Dec 28;377(26):2531-2544. doi: 10.1056/NEJMoa1707447. Epub 2017 Dec 10.
  • Xu Y, Yang Z, Horan LH, Zhang P, Liu L, Zimdahl B, Green S, Lu J, Morales JF, Barrett DM, Grupp SA, Chan VW, Liu H, Liu C. A novel antibody-TCR (AbTCR) platform combines Fab-based antigen recognition with gamma/delta-TCR signaling to facilitate T-cell cytotoxicity with low cytokine release. Cell Discov. 2018 Nov 20;4:62. doi: 10.1038/s41421-018-0066-6. eCollection 2018.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: January 15, 2021) 		18
Original Estimated Enrollment  ICMJE
 (submitted: July 8, 2019) 		50
Estimated Study Completion Date  ICMJE July 1, 2022
Estimated Primary Completion Date July 1, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Patient or his or her legal guardian voluntarily participates in and signs an informed consent form.
  2. Male or female, aged 18 to 75 years (including 18 and 75 years old).

  3. Pathological and histological examination confirmed CD19+ B-cell malignancies, and patients met the following criteria for refractory or relapsed B-cell malignancies.

    A. Refractory/relapsed B-cell lymphoblastic leukemia (Meeting one of the following) i. Recurrence within 6 months after first remission. ii. Primary refractory disease which cannot achieve complete remission (CR) after 2 cycles of standardized chemotherapy regimen.

    iii. Failure to achieve CR or relapse after one line or multiple lines of salvage chemotherapy.

    iv. Not suitable for hematopoietic stem cell transplantation (HSCT), or abandon HSCT due to various restrictions, or relapse after HSCT.

    B. Refractory/relapsed B-cell lymphoma (Meeting 1 of the first 4 items plus item 5) i. Tumor shrinkage less than 50% or disease progression after 4 cycles of standard chemotherapy.

    ii. Achieved CR after standard chemotherapy, but relapsed within 6 months. iii. Two or more relapses after CR. iv. Not suitable for HSCT, or abandon HSCT due to various restrictions, or relapse after HSCT.

    v. Subjects must have received adequate treatment in the past, including anti-CD20 monoclonal antibody and combination chemotherapy with anthracyclines.

  4. Having a measurable or evaluable lesion:

    A. Patients with lymphoma require a single lesion≥15mm or 2 or more lesions≥10mm.

    B. Patients with leukemia require persistent positive or positive relapse of bone marrow MRD.

  5. Patient's main organs functioning well:

    A. Liver function: ALT/AST < 3 times the upper limit of normal (ULN) and total bilirubin≤34.2μmol/L.

    B. Renal function: Creatinine < 220μmol/L. C. Pulmonary function: Indoor oxygen saturation≥95%. D. Cardiac Function: Left ventricular ejection fraction (LVEF) ≥40%.

  6. Patients did not receive any antitumor treatments such as chemotherapy, radiotherapy and immunotherapy within 4 weeks before enrollment, and the toxicity related to previous treatments had returned to < 1 level at enrollment (except for low grade toxicity such as alopecia).
  7. Patients' peripheral superficial venous blood flow smoothly, which can meet the needs of intravenous drip.
  8. ECOG score≤ 2, estimated survival time≥3 months.

Exclusion Criteria:

  1. Women who are pregnant or breastfeeding.
  2. Women of child-bearing potential and all male participants can't use effective methods of contraception for at least 12 months following infusion.
  3. Patients fail to collect enough PBMC.
  4. Patients with other uncontrolled diseases, such as active infections.
  5. Active replication of hepatitis B or active hepatitis C.
  6. Known HIV positive patients.
  7. Patients with active autoimmune diseases requiring systemic immunosuppressive therapy.
  8. Participants with other active malignancies (except non-melanoma skin cancer and cervical cancer) within three years. Patients with a history of successfully-treated tumors with no sign of recurrence in the last two years may be enrolled.
  9. Patients with severe mental disorder or disorders of consciousness.

  10. Organ failure:

    A. Heart: Patients with NYHA class III or higher cardiac failure, or with malignant arrhythmia.

    B. Liver: Patients with Wuhan Conference Classification (1983) class III or higher liver failure.

    C. Kidney: patients with 3rd stage and above kidney failure.

  11. Patients use glucocorticoid or another immune inhibitor in two weeks.
  12. Patients with insufficient T cells or T cell transfection problem.
  13. Patients who need immediate treatment to control tumor progression or relieve tumor burden.
  14. Patients took other clinical treatments within 6 weeks.
  15. Patients with drug addiction.
  16. Patients with poor treatment compliance or difficult to communicate and other problems.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 75 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Yu Hu, M.D., Ph.D 86 13986183871 dr_huyu@126.com
Contact: Heng Mei, M.D., Ph.D 86 13886160811 hmei@hust.edu.cn
Listed Location Countries  ICMJE China
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04014894
Other Study ID Numbers  ICMJE ET019003-T
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party MEI HENG, Wuhan Union Hospital, China
Study Sponsor  ICMJE Wuhan Union Hospital, China
Collaborators  ICMJE Eureka(Beijing) Biotechnology Co., Ltd.
Investigators  ICMJE
Principal Investigator: Heng Mei, M.D., Ph.D Wuhan Union Hospital, China
PRS Account Wuhan Union Hospital, China
Verification Date April 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP

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