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出境医 / 临床实验 / Preemptive Infusion of Donor Lymphocytes Depleted of TCR + T Cells + CD19+ B Cells Following ASCT

Preemptive Infusion of Donor Lymphocytes Depleted of TCR + T Cells + CD19+ B Cells Following ASCT

Study Description
Brief Summary:
The purpose of this study is to reduce the risk of cancer relapse by giving a donor lymphocyte infusion (DLI) to boost the immune system early after a stem cell transplant so that leukemia cells that escaped chemotherapy can be detected and killed. This DLI will contain mostly lymphocytes that have graft versus tumor effect with low risk of graft versus host disease. Because the process of giving a DLI in the first four weeks after a transplant has not been approved by the Food and Drug Administration (FDA), this study in investigational (experimental).

Condition or disease Intervention/treatment Phase
Allogeneic Stem Cell Transplant Candidate Acute Myeloid/Lymphoblastic Leukemia Myelodysplastic Syndrome Myeloproliferative Neoplasm Lymphoproliferative Disorders Biological: Cellular therapy product Phase 1

Detailed Description:

The primary objective of this study is to investigate if donor lymphocytes depleted of TCR-αβ T cells and B cells can be infused on Day 28 following allogeneic stem cell transplantation without inducing Grade III-IV graft versus host disease, Grade II GVHD requiring systemic treatment and or new onset, severe neutropenia requiring growth factor support.

This study also seeks to characterize the lymphocyte subsets obtained following depletion of TCR-αβ T cells and B cells from non-mobilized, leukapheresis products.

Additionally, this study will attempt to describe occurrence of disease relapse and to describe the occurrence of post-transplant re- activation and/or infections with viruses such as CMV, and EBV.

Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 10 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Intervention Model Description: This is a Phase I, pilot study designed to treat 10 participants with the donor NK/γδ T cell-enriched product on transplant Day 28.
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Preemptive Infusion of Donor Lymphocytes Depleted of TCR (Alpha-beta) + T Cells and CD19+ B Cells Following Allogeneic Stem Cell Transplantation
Estimated Study Start Date : June 2021
Estimated Primary Completion Date : June 2022
Estimated Study Completion Date : June 2023
Arms and Interventions
Arm Intervention/treatment
Experimental: NK/γδ T cell-enriched cell therapy product

This study will treat 10 participants with the donor NK/TCR-γδ T cell product. Of those 10 participants, 5 would have 10/10 HLA matched sibling donors (MSD) while 5 would have partially matched, related (haplo) donors.

  • 27 days post transplant, the participant's donor will undergo a second, non-mobilized leukapheresis to obtain peripheral blood mononuclear cells (PBMCs).
  • Donor PBMCs will be processed next day (Day T+28) to obtain the NK cell/TCRγδ T cell product for same day infusion if the participant remains aGVHD free and clinically stable.
  • Participants will continue routine post-transplant and GVHD monitoring, as well as disease assessment at 56 days, 100 days, 6 months and 1 year following transplant.
  • Blood samples will be obtained on T=0, T+7, 14, 21 and 28 days and then weekly until T + 56 days, then on T+100 days, + 6 months and + 12 months. If immune-mediated adverse events occur (GVHD, CRS etc) additional blood samples will be obtained at onset and resolution.
 Biological: Cellular therapy product

Cellular therapy product: Allogeneic transplant donor lymphocytes, depleted of TCR-αβ T cells and B cells; enriched for NK cells and TCRγδ T cells.

  • Infused using venous catheter on post-transplant Day 28 (+ 7 days).
  • Single infusion of entire lymphocyte product derived from two-blood volume leukapheresis (non-mobilized).
Outcome Measures
Primary Outcome Measures :
  1. Incidence of Grade III-IV GVHD, Grade II GVHD requiring systemic treatment or new onset, severe neutropenia requiring growth factor support at Day 100 and T+6 months. [ Time Frame: up to 30 days after lymphocyte product infusion ]

    This study seeks to measure if donor lymphocytes depleted of TCR-αβ T cells and B cells can be infused on Day 28 following allogeneic stem cell transplantation without inducing Grade III-IV graft versus host disease, Grade II GVHD requiring systemic treatment or new onset, severe neutropenia requiring growth factor support.

    The endpoint associated with this objective is 'incidence of Grade III-IV graft versus host disease, Grade II GVHD requiring systemic treatment or new onset, severe neutropenia requiring growth factor support at Day 100 and T+6 months.'



Secondary Outcome Measures :
  1. Different lymphocyte types in the infused product reported as cells per kilogram body weight of the recipient [ Time Frame: 28 days post-transplant ]
    Number of different lymphocyte types in the infused product measured as cells per kilogram body weight of the recipient

  2. Number of disease relapse events in the first 6 moths following stem cell transplant [ Time Frame: 6 months from start of treatment ]
    To describe occurrence of disease relapse, the number of disease relapse events in the first year following stem cell transplant will be reported.

  3. Number of disease relapse events in the first 1 year following stem cell transplant [ Time Frame: 1 year from start of treatment ]
    To describe occurrence of disease relapse, the number of disease relapse events in the first year following stem cell transplant will be reported.

  4. Average time to disease relapse from date of transplant [ Time Frame: 6 months from start of treatment ]
    To describe occurrence of disease relapse, the average time to disease relapse from date of transplant in the first six months following stem cell transplant will be reported.

  5. Average time to disease relapse from date of transplant [ Time Frame: 1 year from start of treatment ]
    To describe occurrence of disease relapse, the average time to disease relapse from date of transplant in the first year following stem cell transplant will be reported.

  6. Occurrence of reactivated Epstein Barr Virus (EBV) and/or Cytomegalovirus viremia (CMV) as measured by number of study subjects developing measurable viremia [ Time Frame: 6 months from start of treatment ]
    To describe the occurrence of post-transplant re- activation and/or infections with viruses such as CMV, and/or EBV, the number of study subjects developing measurable viremia will be reported

  7. Average time to first occurrence of reactivated EBV and/or CMV [ Time Frame: 6 months from start of treatment ]
    To describe the occurence of post-transplant re- activation and/or infections with viruses such as CMV, and/or EBV, median time to first occurrence of reactivated EBV and/or CMV will be reported.


Eligibility Criteria
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Ages Eligible for Study:   1 Year and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Subjects must have histologic or cytologic confirmation of ANY hematologic malignancy
  • Allogeneic stem cell transplant is indicated as management of underlying hematologic malignancy.
  • Participant has organ function (cardiac, lung and liver) considered adequate to undergo conditioning chemotherapy and allogeneic stem cell transplant in the assessment of the clinical program
  • Participant has a 10/10 HLA-matched sibling donor OR has a HLA-haploidentical donor available (in the absence of a 10/10 HLA matched unrelated donor)
  • The related transplant donor is willing, available and consents to undergo a second, non-mobilized leukapheresis for the procurement of donor lymphocytes
  • The related transplant donor is 18 years of age or older
  • Subjects (or their parents if participant is younger than 18 years old) must have the ability to understand and the willingness to sign a written informed consent document or provide assent.

Exclusion Criteria:

  • Subject is unwilling to receive a prophylactic donor lymphocyte infusion per study protocol.
  • The related donor is unwilling or unavailable to undergo a second, non- mobilized leukapheresis for the procurement of donor lymphocytes.
  • Women of child-bearing potential and men must agree to use adequate contraception (double barrier method of birth control or abstinence) 4 weeks prior to study entry and for the duration of study participation. Women of child-bearing age must have documented negative pregnancy test prior to start of conditioning regimen for stem cell transplantation and a repeat negative pregnancy test prior to infusion of the lymphocyte product.
Contacts and Locations

Contacts
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Contact: Folashade Otegbeye, MD 1-800-641-2422 CTUReferral@UHhospitals.org

Locations
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United States, Ohio
University Hospitals Cleveland Medical Center, Case Comprehensive Cancer Center
Cleveland, Ohio, United States, 44106
Contact: Folashade Otegbeye, MD    800-641-2422    CTUReferral@UHhospitals.org   
Sponsors and Collaborators
Folashade Otegbeye
Investigators
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Principal Investigator: Folashade Otegbeye, MD University Hospitals Cleveland Medical Center, Case Comprehensive Cancer Center
Tracking Information
First Submitted Date  ICMJE May 3, 2019
First Posted Date  ICMJE May 7, 2019
Last Update Posted Date May 10, 2021
Estimated Study Start Date  ICMJE June 2021
Estimated Primary Completion Date June 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 3, 2019) 		Incidence of Grade III-IV GVHD, Grade II GVHD requiring systemic treatment or new onset, severe neutropenia requiring growth factor support at Day 100 and T+6 months. [ Time Frame: up to 30 days after lymphocyte product infusion ]
This study seeks to measure if donor lymphocytes depleted of TCR-αβ T cells and B cells can be infused on Day 28 following allogeneic stem cell transplantation without inducing Grade III-IV graft versus host disease, Grade II GVHD requiring systemic treatment or new onset, severe neutropenia requiring growth factor support. The endpoint associated with this objective is 'incidence of Grade III-IV graft versus host disease, Grade II GVHD requiring systemic treatment or new onset, severe neutropenia requiring growth factor support at Day 100 and T+6 months.'
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: May 3, 2019)
  • Different lymphocyte types in the infused product reported as cells per kilogram body weight of the recipient [ Time Frame: 28 days post-transplant ]
    Number of different lymphocyte types in the infused product measured as cells per kilogram body weight of the recipient
  • Number of disease relapse events in the first 6 moths following stem cell transplant [ Time Frame: 6 months from start of treatment ]
    To describe occurrence of disease relapse, the number of disease relapse events in the first year following stem cell transplant will be reported.
  • Number of disease relapse events in the first 1 year following stem cell transplant [ Time Frame: 1 year from start of treatment ]
    To describe occurrence of disease relapse, the number of disease relapse events in the first year following stem cell transplant will be reported.
  • Average time to disease relapse from date of transplant [ Time Frame: 6 months from start of treatment ]
    To describe occurrence of disease relapse, the average time to disease relapse from date of transplant in the first six months following stem cell transplant will be reported.
  • Average time to disease relapse from date of transplant [ Time Frame: 1 year from start of treatment ]
    To describe occurrence of disease relapse, the average time to disease relapse from date of transplant in the first year following stem cell transplant will be reported.
  • Occurrence of reactivated Epstein Barr Virus (EBV) and/or Cytomegalovirus viremia (CMV) as measured by number of study subjects developing measurable viremia [ Time Frame: 6 months from start of treatment ]
    To describe the occurrence of post-transplant re- activation and/or infections with viruses such as CMV, and/or EBV, the number of study subjects developing measurable viremia will be reported
  • Average time to first occurrence of reactivated EBV and/or CMV [ Time Frame: 6 months from start of treatment ]
    To describe the occurence of post-transplant re- activation and/or infections with viruses such as CMV, and/or EBV, median time to first occurrence of reactivated EBV and/or CMV will be reported.
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 Preemptive Infusion of Donor Lymphocytes Depleted of TCR + T Cells + CD19+ B Cells Following ASCT
Official Title  ICMJE Preemptive Infusion of Donor Lymphocytes Depleted of TCR (Alpha-beta) + T Cells and CD19+ B Cells Following Allogeneic Stem Cell Transplantation
Brief Summary The purpose of this study is to reduce the risk of cancer relapse by giving a donor lymphocyte infusion (DLI) to boost the immune system early after a stem cell transplant so that leukemia cells that escaped chemotherapy can be detected and killed. This DLI will contain mostly lymphocytes that have graft versus tumor effect with low risk of graft versus host disease. Because the process of giving a DLI in the first four weeks after a transplant has not been approved by the Food and Drug Administration (FDA), this study in investigational (experimental).
Detailed Description

The primary objective of this study is to investigate if donor lymphocytes depleted of TCR-αβ T cells and B cells can be infused on Day 28 following allogeneic stem cell transplantation without inducing Grade III-IV graft versus host disease, Grade II GVHD requiring systemic treatment and or new onset, severe neutropenia requiring growth factor support.

This study also seeks to characterize the lymphocyte subsets obtained following depletion of TCR-αβ T cells and B cells from non-mobilized, leukapheresis products.

Additionally, this study will attempt to describe occurrence of disease relapse and to describe the occurrence of post-transplant re- activation and/or infections with viruses such as CMV, and EBV.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Intervention Model Description:
This is a Phase I, pilot study designed to treat 10 participants with the donor NK/γδ T cell-enriched product on transplant Day 28.
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Allogeneic Stem Cell Transplant Candidate
  • Acute Myeloid/Lymphoblastic Leukemia
  • Myelodysplastic Syndrome
  • Myeloproliferative Neoplasm
  • Lymphoproliferative Disorders
Intervention  ICMJE Biological: Cellular therapy product

Cellular therapy product: Allogeneic transplant donor lymphocytes, depleted of TCR-αβ T cells and B cells; enriched for NK cells and TCRγδ T cells.

  • Infused using venous catheter on post-transplant Day 28 (+ 7 days).
  • Single infusion of entire lymphocyte product derived from two-blood volume leukapheresis (non-mobilized).
Study Arms  ICMJE Experimental: NK/γδ T cell-enriched cell therapy product

This study will treat 10 participants with the donor NK/TCR-γδ T cell product. Of those 10 participants, 5 would have 10/10 HLA matched sibling donors (MSD) while 5 would have partially matched, related (haplo) donors.

  • 27 days post transplant, the participant's donor will undergo a second, non-mobilized leukapheresis to obtain peripheral blood mononuclear cells (PBMCs).
  • Donor PBMCs will be processed next day (Day T+28) to obtain the NK cell/TCRγδ T cell product for same day infusion if the participant remains aGVHD free and clinically stable.
  • Participants will continue routine post-transplant and GVHD monitoring, as well as disease assessment at 56 days, 100 days, 6 months and 1 year following transplant.
  • Blood samples will be obtained on T=0, T+7, 14, 21 and 28 days and then weekly until T + 56 days, then on T+100 days, + 6 months and + 12 months. If immune-mediated adverse events occur (GVHD, CRS etc) additional blood samples will be obtained at onset and resolution.
Intervention: Biological: Cellular therapy product
Publications * Not Provided

*   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 Not yet recruiting
Estimated Enrollment  ICMJE
 (submitted: May 3, 2019) 		10
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE June 2023
Estimated Primary Completion Date June 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Subjects must have histologic or cytologic confirmation of ANY hematologic malignancy
  • Allogeneic stem cell transplant is indicated as management of underlying hematologic malignancy.
  • Participant has organ function (cardiac, lung and liver) considered adequate to undergo conditioning chemotherapy and allogeneic stem cell transplant in the assessment of the clinical program
  • Participant has a 10/10 HLA-matched sibling donor OR has a HLA-haploidentical donor available (in the absence of a 10/10 HLA matched unrelated donor)
  • The related transplant donor is willing, available and consents to undergo a second, non-mobilized leukapheresis for the procurement of donor lymphocytes
  • The related transplant donor is 18 years of age or older
  • Subjects (or their parents if participant is younger than 18 years old) must have the ability to understand and the willingness to sign a written informed consent document or provide assent.

Exclusion Criteria:

  • Subject is unwilling to receive a prophylactic donor lymphocyte infusion per study protocol.
  • The related donor is unwilling or unavailable to undergo a second, non- mobilized leukapheresis for the procurement of donor lymphocytes.
  • Women of child-bearing potential and men must agree to use adequate contraception (double barrier method of birth control or abstinence) 4 weeks prior to study entry and for the duration of study participation. Women of child-bearing age must have documented negative pregnancy test prior to start of conditioning regimen for stem cell transplantation and a repeat negative pregnancy test prior to infusion of the lymphocyte product.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 1 Year and older   (Child, Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Folashade Otegbeye, MD 1-800-641-2422 CTUReferral@UHhospitals.org
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03939585
Other Study ID Numbers  ICMJE CASE1Z19
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: Individual participant data that underlie or influence the results observed from the study
Supporting Materials: Study Protocol
Supporting Materials: Statistical Analysis Plan (SAP)
Supporting Materials: Clinical Study Report (CSR)
Supporting Materials: Analytic Code
Time Frame: Beginning 3 months and ending 5 years following article publication
Access Criteria: Investigators who provide a methodologically sound proposal for use of requested data
Responsible Party Folashade Otegbeye, Case Comprehensive Cancer Center
Study Sponsor  ICMJE Folashade Otegbeye
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Folashade Otegbeye, MD University Hospitals Cleveland Medical Center, Case Comprehensive Cancer Center
PRS Account Case Comprehensive Cancer Center
Verification Date May 2021

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

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