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出境医 / 临床实验 / Safety and Efficacy of Anti-CD123 CAR-T Therapy in Patients With Refractory/ Relapsed CD123+ Acute Myeloid Leukemia.

Safety and Efficacy of Anti-CD123 CAR-T Therapy in Patients With Refractory/ Relapsed CD123+ Acute Myeloid Leukemia.

Study Description
Brief Summary:
This is a single-center, open-label, single-arm study to evaluate the safety and efficacy of anti-CD123 CAR-T cells in patients with refractory/relapsed CD123+ Acute Myeloid Leukemia.

Condition or disease Intervention/treatment Phase
CD123+ Acute Myeloid Leukemia Biological: Third-generation anti-CD123 CAR-T cells Phase 1

Detailed Description:
CD123 is a transmembrane subunit of the IL-3 receptor expressed on AML blasts. The investigators have conducted a third generationCD123-targeted CAR containing CD137 and CD28 costimulatory domains.This study aims to evaluate the safety and efficacy of anti-CD123 CAR-T cells in patients with relapsed/refractory CD123+ Acute Myeloid Leukemia.
Study Design
Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 50 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.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: Single-center, Open-label, Single-arm Clinical Study of Efficacy and Safety of Anti-CD123 CAR-T Therapy in Patients With Refractory/Relapsed CD123+ Acute Myeloid Leukemia.
Actual Study Start Date : July 6, 2019
Estimated Primary Completion Date : July 1, 2021
Estimated Study Completion Date : July 1, 2022
Arms and Interventions
Arm Intervention/treatment
Experimental: CD123+ Acute Myeloid Leukemia
Patients will receive CD123-targeted CAR-T cells in the dose-climbing trial. Each dose group has 3 patients and the the maximum dose can be extended.
 Biological: Third-generation anti-CD123 CAR-T cells
From the minimum dose, 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.
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 anti-CD123 CAR-T Therapy in patients with refractory/relapsed CD123+ Acute Myeloid Leukemia [ 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 anti-CD123 CAR-T cells in patients with refractory/relapsed CD123+ Acute Myeloid Leukemia [ Time Frame: 3 years ]
    OS will be assessed from the first CAR-T cell infusion to death or last follow-up (censored).

  3. Duration of Response(DOR) of anti-CD123 CAR-T cells in patients with refractory/relapsed CD123+ Acute Myeloid Leukemia [ Time Frame: 3 years ]
    DOR will be assessed from the first CAR-T cell infusion to death or last follow-up (censored).

  4. Progress-free survival(PFS) of anti-CD123 CAR-T cells in patients with refractory/relapsed CD123+ Acute Myeloid Leukemia [ Time Frame: 3 years ]
    PFS will be assessed from the first CAR-T cell infusion to death or last follow-up (censored).

  5. Rate of anti-CD123 CAR-T cells in bone marrow cells and peripheral blood cells [ Time Frame: 3 years ]
    In vivo (bone marrow and peripheral blood) rate and quantity of anti-CD123 CAR-T cells were determined by means of flow cytometry.

  6. Quantity of anti-CD123 CAR copies in bone marrow cells and peripheral blood cells [ Time Frame: 3 years ]
    In vivo (bone marrow and peripheral blood) quantity of anti-CD123 CAR copies were determined by means of qPCR.


Eligibility Criteria
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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Pathological and histological examination confirmed CD123+ refractory or relapsed Acute Myeloid Leukemia.

    A. Diagnostic criteria for recurrent AML: After complete remission (CR), leukemia cells or bone marrow primordial cells > 0.050 (except for bone marrow regeneration after consolidation chemotherapy) or extramedullary leukemia cell infiltration appears again in peripheral blood.

    B．Diagnostic criteria for refractory AML(Meeting one of the following)

    i. ineffectiveness after the first standard regimen treatment of 2 courses.

    ii. patients relapse within 12 months after consolidation and intensive treatment after CR.

    iii. Patients relapse 12 months later and fail to respond to conventional chemotherapy.

    iv. Patients with two or more recurrences.

    v. Patients with persistent extramedullary leukemia.

    vi. Patients with recurrence after CR and unsuitable for HSCT (auto/allo-HSCT).

  2. Aged 18 to 70 years (including 18 and 70 years old).
  3. At least one measurable or evaluable lesion：AML patients with positive or relapsed positive bone marrow MRD.
  4. ECOG≤ 2 and expected lifetime ≥3 months.

  5. Adequate organ function:

    A. Liver function: ALT/AST≤3 ULN. Total bilirubin≤2 ULN.

    B. Renal function: eGFR> 60 mL/min/1.73 m2, or creatinine clearance ≥45mL/min.

    C. Lung function: Carbon Monoxide (DLCO) or Forced Expiratory Volume in the first second (FEV1) > 45% predicted.

    D. Cardiac function: LVEF ≥ 50%.

  6. The patients did not receive any anticancer treatments such as chemotherapy, radiotherapy and immunotherapy (such as immunosuppressive drugs) within 4 weeks before admission, and the toxicity related to previous treatments had returned to < 1 level at admission (except for low toxicity such as alopecia).
  7. Women of child-bearing potential and all male participants must use effective methods of contraception for at least 12 months after infusion.
  8. Informed Consent/Assent: All subjects must have the ability to understand and the willingness to sign a written informed consent.

Exclusion Criteria:

  1. Women who are pregnant (urine/blood pregnancy test positive) or lactating.
  2. Male or female with a conception plan in the past 1 years.
  3. Patients cannot guarantee effective contraception (condom or contraceptives, etc.) within 1 years after enrollment.
  4. Uncontrolled infectious disease within 4 weeks prior to enrollment.
  5. Active hepatitis B/C virus.
  6. HIV infected patients.
  7. Suffering from a serious autoimmune disease or immunodeficiency disease.
  8. The patient is allergic and is allergic to macromolecular biopharmaceuticals such as antibodies or cytokines.
  9. The patient participated in other clinical trials within 6 weeks prior to enrollment.
  10. Systemic use of hormones within 4 weeks prior to enrollment (except for patients with inhaled corticosteroids).
  11. Suffering from mental illness.
  12. Patient has drug abuse/addiction.
  13. Central nervous system involvement.
  14. According to the investigator's judgment, the patient has other unsuitable grouping conditions.
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, M.D., Ph.D    86-13986183871    dr_huyu@126.com   
Contact: Heng Mei, M.D., Ph.D    86-13886160811    hmei@hust.edu.cn   
Sponsors and Collaborators
Wuhan Union Hospital, China
Wuhan Bio-Raid 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 August 7, 2019
Actual Study Start Date  ICMJE July 6, 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 anti-CD123 CAR-T Therapy in patients with refractory/relapsed CD123+ Acute Myeloid Leukemia [ 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 anti-CD123 CAR-T cells in patients with refractory/relapsed CD123+ Acute Myeloid Leukemia [ Time Frame: 3 years ]
    OS will be assessed from the first CAR-T cell infusion to death or last follow-up (censored).
  • Duration of Response(DOR) of anti-CD123 CAR-T cells in patients with refractory/relapsed CD123+ Acute Myeloid Leukemia [ Time Frame: 3 years ]
    DOR will be assessed from the first CAR-T cell infusion to death or last follow-up (censored).
  • Progress-free survival(PFS) of anti-CD123 CAR-T cells in patients with refractory/relapsed CD123+ Acute Myeloid Leukemia [ Time Frame: 3 years ]
    PFS will be assessed from the first CAR-T cell infusion to death or last follow-up (censored).
  • Rate of anti-CD123 CAR-T cells in bone marrow cells and peripheral blood cells [ Time Frame: 3 years ]
    In vivo (bone marrow and peripheral blood) rate and quantity of anti-CD123 CAR-T cells were determined by means of flow cytometry.
  • Quantity of anti-CD123 CAR copies in bone marrow cells and peripheral blood cells [ Time Frame: 3 years ]
    In vivo (bone marrow and peripheral blood) quantity of anti-CD123 CAR 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 Safety and Efficacy of Anti-CD123 CAR-T Therapy in Patients With Refractory/ Relapsed CD123+ Acute Myeloid Leukemia.
Official Title  ICMJE Single-center, Open-label, Single-arm Clinical Study of Efficacy and Safety of Anti-CD123 CAR-T Therapy in Patients With Refractory/Relapsed CD123+ Acute Myeloid Leukemia.
Brief Summary This is a single-center, open-label, single-arm study to evaluate the safety and efficacy of anti-CD123 CAR-T cells in patients with refractory/relapsed CD123+ Acute Myeloid Leukemia.
Detailed Description CD123 is a transmembrane subunit of the IL-3 receptor expressed on AML blasts. The investigators have conducted a third generationCD123-targeted CAR containing CD137 and CD28 costimulatory domains.This study aims to evaluate the safety and efficacy of anti-CD123 CAR-T cells in patients with relapsed/refractory CD123+ Acute Myeloid Leukemia.
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.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 CD123+ Acute Myeloid Leukemia
Intervention  ICMJE Biological: Third-generation anti-CD123 CAR-T cells
From the minimum dose, 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.
Study Arms  ICMJE Experimental: CD123+ Acute Myeloid Leukemia
Patients will receive CD123-targeted CAR-T cells in the dose-climbing trial. Each dose group has 3 patients and the the maximum dose can be extended.
Intervention: Biological: Third-generation anti-CD123 CAR-T cells
Publications *
  • Hansrivijit P, Gale RP, Barrett J, Ciurea SO. Cellular therapy for acute myeloid Leukemia - Current status and future prospects. Blood Rev. 2019 Sep;37:100578. doi: 10.1016/j.blre.2019.05.002. Epub 2019 May 11. Review.
  • Arcangeli S, Rotiroti MC, Bardelli M, Simonelli L, Magnani CF, Biondi A, Biagi E, Tettamanti S, Varani L. Balance of Anti-CD123 Chimeric Antigen Receptor Binding Affinity and Density for the Targeting of Acute Myeloid Leukemia. Mol Ther. 2017 Aug 2;25(8):1933-1945. doi: 10.1016/j.ymthe.2017.04.017. Epub 2017 May 4.
  • Cartellieri M, Feldmann A, Koristka S, Arndt C, Loff S, Ehninger A, von Bonin M, Bejestani EP, Ehninger G, Bachmann MP. Switching CAR T cells on and off: a novel modular platform for retargeting of T cells to AML blasts. Blood Cancer J. 2016 Aug 12;6(8):e458. doi: 10.1038/bcj.2016.61.
  • Tettamanti S, Biondi A, Biagi E, Bonnet D. CD123 AML targeting by chimeric antigen receptors: A novel magic bullet for AML therapeutics? Oncoimmunology. 2014 May 14;3:e28835. eCollection 2014.
  • Tasian SK, Kenderian SS, Shen F, Ruella M, Shestova O, Kozlowski M, Li Y, Schrank-Hacker A, Morrissette JJD, Carroll M, June CH, Grupp SA, Gill S. Optimized depletion of chimeric antigen receptor T cells in murine xenograft models of human acute myeloid leukemia. Blood. 2017 Apr 27;129(17):2395-2407. doi: 10.1182/blood-2016-08-736041. Epub 2017 Feb 28.
  • Mardiros A, Dos Santos C, McDonald T, Brown CE, Wang X, Budde LE, Hoffman L, Aguilar B, Chang WC, Bretzlaff W, Chang B, Jonnalagadda M, Starr R, Ostberg JR, Jensen MC, Bhatia R, Forman SJ. T cells expressing CD123-specific chimeric antigen receptors exhibit specific cytolytic effector functions and antitumor effects against human acute myeloid leukemia. Blood. 2013 Oct 31;122(18):3138-48. doi: 10.1182/blood-2012-12-474056. Epub 2013 Sep 12.

*   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: July 8, 2019) 		50
Original Estimated Enrollment  ICMJE Same as current
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. Pathological and histological examination confirmed CD123+ refractory or relapsed Acute Myeloid Leukemia.

    A. Diagnostic criteria for recurrent AML: After complete remission (CR), leukemia cells or bone marrow primordial cells > 0.050 (except for bone marrow regeneration after consolidation chemotherapy) or extramedullary leukemia cell infiltration appears again in peripheral blood.

    B．Diagnostic criteria for refractory AML(Meeting one of the following)

    i. ineffectiveness after the first standard regimen treatment of 2 courses.

    ii. patients relapse within 12 months after consolidation and intensive treatment after CR.

    iii. Patients relapse 12 months later and fail to respond to conventional chemotherapy.

    iv. Patients with two or more recurrences.

    v. Patients with persistent extramedullary leukemia.

    vi. Patients with recurrence after CR and unsuitable for HSCT (auto/allo-HSCT).

  2. Aged 18 to 70 years (including 18 and 70 years old).
  3. At least one measurable or evaluable lesion：AML patients with positive or relapsed positive bone marrow MRD.
  4. ECOG≤ 2 and expected lifetime ≥3 months.

  5. Adequate organ function:

    A. Liver function: ALT/AST≤3 ULN. Total bilirubin≤2 ULN.

    B. Renal function: eGFR> 60 mL/min/1.73 m2, or creatinine clearance ≥45mL/min.

    C. Lung function: Carbon Monoxide (DLCO) or Forced Expiratory Volume in the first second (FEV1) > 45% predicted.

    D. Cardiac function: LVEF ≥ 50%.

  6. The patients did not receive any anticancer treatments such as chemotherapy, radiotherapy and immunotherapy (such as immunosuppressive drugs) within 4 weeks before admission, and the toxicity related to previous treatments had returned to < 1 level at admission (except for low toxicity such as alopecia).
  7. Women of child-bearing potential and all male participants must use effective methods of contraception for at least 12 months after infusion.
  8. Informed Consent/Assent: All subjects must have the ability to understand and the willingness to sign a written informed consent.

Exclusion Criteria:

  1. Women who are pregnant (urine/blood pregnancy test positive) or lactating.
  2. Male or female with a conception plan in the past 1 years.
  3. Patients cannot guarantee effective contraception (condom or contraceptives, etc.) within 1 years after enrollment.
  4. Uncontrolled infectious disease within 4 weeks prior to enrollment.
  5. Active hepatitis B/C virus.
  6. HIV infected patients.
  7. Suffering from a serious autoimmune disease or immunodeficiency disease.
  8. The patient is allergic and is allergic to macromolecular biopharmaceuticals such as antibodies or cytokines.
  9. The patient participated in other clinical trials within 6 weeks prior to enrollment.
  10. Systemic use of hormones within 4 weeks prior to enrollment (except for patients with inhaled corticosteroids).
  11. Suffering from mental illness.
  12. Patient has drug abuse/addiction.
  13. Central nervous system involvement.
  14. According to the investigator's judgment, the patient has other unsuitable grouping conditions.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 70 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 NCT04014881
Other Study ID Numbers  ICMJE WHUH-CART-CD123-01
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 Wuhan Bio-Raid 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 August 2019

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

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