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出境医 / 临床实验 / Irradiation-based Myeloablative Conditioning Followed by Treg/Tcon Immunotherapy in HSCT

Irradiation-based Myeloablative Conditioning Followed by Treg/Tcon Immunotherapy in HSCT

Study Description
Brief Summary:
To evaluate if hyper-fractionated TBI or TMLI followed by Treg/Tcon adoptive immunotherapy improve cGvHD/disease free survival after allogeneic HSCT in patients affected by high-risk acute leukemias or other hematologic malignancy where HSCT is indicated.

Condition or disease Intervention/treatment Phase
Acute Myeloid Leukemia Acute Lymphoid Leukemia Myeloproliferative Disorders Lymphoma Multiple Myeloma Other Hematologic Malignant Neoplasms Biological: High dose irradiation conditioning + Treg/Tcon Phase 2

Detailed Description:
Improving cGvHD/disease free survival in patients with high-risk acute leukemias or other hematologic malignancy where HSCT is indicated with the use of a regulatory T cell based protocol. Hyper-fractionated Total Body Irradiation or Total Marrow and Lymphoid Irradiation based conditioning will be followed by the infusion of T regulatory and T conventional cell adoptive immunotherapy and a purified CD34+ hematopoietic stem cell graft. Incidence of Non Relapse Mortality, Relapse, acute Graft versus Host Disease, chronic Graft versus Host Disease, as well as probability of cGvHD/disease free survival will be assessed in patient subpopulations separated according to HLA-matching with the donor (HLA-matched HSCT and HLA-haploidentical HSCT) and type of disease (acute myeloid leukemia, acute lymphoid leukemia, lymphoma, multiple myeloma, myeloproliferative disease, and other).
Study Design
Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 80 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Antileukemic Activity of Allogeneic Hematopoietic Stem Cell Transplantation With Fractionated Total Body Irradiation or Total Marrow and Lymph Node Irradiation Followed by Adoptive Immunotherapy With Regulatory and Conventional T Cells
Study Start Date : February 2014
Estimated Primary Completion Date : February 28, 2023
Estimated Study Completion Date : February 28, 2023
Arms and Interventions
Arm Intervention/treatment
Experimental: High dose irradiation conditioning + Treg/Tcon
High dose irradiation based conditioning regimens followed by infusion of donor regulatory and conventional T cells and purified CD34+ hematopoietic stem cell transplantation
 Biological: High dose irradiation conditioning + Treg/Tcon
High dose irradiation based conditioning regimens followed by infusion of donor regulatory and conventional T cells and purified CD34+ hematopoietic stem cell transplantation
Outcome Measures
Primary Outcome Measures :
  1. chronic GvHD/relapse-free survival [ Time Frame: 2 years ]
    To evaluate if irradiation based myeloablative conditioning followed by Treg/Tcon adoptive immunotherapy improve chronic GvHD/relapse-free survival (GRFS) after allogeneic HSCT in patients affected by acute leukemias or other hematologic malignancies where HSCT is indicated. GRFS will be assessed in subgroups of patients separated according to HLA-matching with the donor and type of disease (acute myeloid lekemia, acute lymphoid leukemia, other)


Secondary Outcome Measures :
  1. full donor-type engraftment [ Time Frame: 30 days ]
    neutrophil and platelet engraftment measured by neutrophil counts >500/mmc for 3 consecutive days and platelets count >20000/mmc with 7 consecutive without platelet transfusion


Other Outcome Measures:
  1. cumulative incidence of grades ≥ 2 acute GvHD [ Time Frame: 6 months ]
    cumulative incidence of grades ≥ 2 acute GvHD according to NIH consesus criteria

  2. cumulative incidence of extensive chronic GvHD [ Time Frame: 2 years ]
    cumulative incidence of extensive chronic GvHD according to revised NIH consesus criteria (Jagasia et al. BBMT 2015)

  3. cumulative incidence of non-relapse mortality [ Time Frame: 2 years ]
    cumulative incidence of non-relapse mortality, defined as death by any cause in the absence of relapse, as competitive risk versus relapse

  4. cumulative incidence of relapse [ Time Frame: 2 years ]
    cumulative incidence of relapse, defined as disease recurrence according to marrow morphology, flow cytometry, cytogenetics, fluorescence in situ hybridization and/or polymerase chain reaction, as competitive risk versus non-relapse mortality


Eligibility Criteria
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Ages Eligible for Study:   up to 75 Years   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • AML and ALL in complete remission and with high-risk of relapse
  • AML and ALL primarily chemoresistant or relapsed;
  • Chronic Myeloid Leukemia in accelerated or blastic phase;

  • Patients affected by

    • Multiple myeloma,
    • Non Hodgkin lymphoma,
    • Hodgkin lymphoma,
    • Chronic myeloproliferative syndrome,
    • Chronic Lymphoid Leukemia,
    • Other Hematological malignancy at high-risk of relapse or detectable disease and where a HSCT is indicated.
  • Age <75 years
  • ECOG ≤ 2
  • Acceptable lung, liver, kidney, and heart function and absence of relevant psichiatric diseases
  • Signature of the informed consent

Exclusion Criteria:

  • Age >75 years
  • ECOG > 2
  • Not acceptable lung, liver, kidney, and heart function and presence of relevant psichiatric diseases
  • Pregnancy
  • No signature of the informed consent
Contacts and Locations

Contacts
Layout table for location contacts
Contact: Antonio Pierini, MD, PhD +390755784147 antonio.pierini@unipg.it
Contact: Mara Merluzzi, MBioTech +393482200239 maramerluzzi@libero.it

Locations
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Italy
University of Perugia Recruiting
Perugia, PG, Italy, 06132
Contact: Antonio Pierini, MD, PhD    +390755784147    antonio.pierini@unipg.it   
Contact: Mara Merluzzi, MBioTech    +393482200239    maramerluzzi@libero.it   
Principal Investigator: Cynthia Aristei, MD         
Principal Investigator: Maurizio Caniglia, MD         
Sub-Investigator: Alessandra Carotti, MD         
Sub-Investigator: Franca Falzetti, MD         
Sub-Investigator: Antonio Pierini, MD         
Sub-Investigator: Loredana Ruggeri, MD         
Sub-Investigator: Adelmo Terenzi, MD         
Sub-Investigator: Simonetta Saldi, MD         
Sub-Investigator: Ilaria Capolsini, MD         
Sub-Investigator: Elena Mastrodicasa, MD         
Sub-Investigator: Maria Speranza Massei, MD         
Sponsors and Collaborators
University Of Perugia
Investigators
Layout table for investigator information
Principal Investigator: Andrea Velardi, MD, PhD University Of Perugia
Tracking Information
First Submitted Date  ICMJE June 4, 2019
First Posted Date  ICMJE June 6, 2019
Last Update Posted Date January 13, 2020
Study Start Date  ICMJE February 2014
Estimated Primary Completion Date February 28, 2023   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 8, 2020) 		chronic GvHD/relapse-free survival [ Time Frame: 2 years ]
To evaluate if irradiation based myeloablative conditioning followed by Treg/Tcon adoptive immunotherapy improve chronic GvHD/relapse-free survival (GRFS) after allogeneic HSCT in patients affected by acute leukemias or other hematologic malignancies where HSCT is indicated. GRFS will be assessed in subgroups of patients separated according to HLA-matching with the donor and type of disease (acute myeloid lekemia, acute lymphoid leukemia, other)
Original Primary Outcome Measures  ICMJE
 (submitted: June 4, 2019) 		chronic GvHD and disease free survival [ Time Frame: 1 year ]
To evaluate if hyper-fractionated TBI or TMLI followed by Treg/Tcon adoptive immunotherapy improve cGvHD/disease free survival after allogeneic HSCT in patients affected by high-risk acute leukemias or other hematologic malignancy where HSCT is indicated.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: January 8, 2020) 		full donor-type engraftment [ Time Frame: 30 days ]
neutrophil and platelet engraftment measured by neutrophil counts >500/mmc for 3 consecutive days and platelets count >20000/mmc with 7 consecutive without platelet transfusion
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures
 (submitted: January 8, 2020)
  • cumulative incidence of grades ≥ 2 acute GvHD [ Time Frame: 6 months ]
    cumulative incidence of grades ≥ 2 acute GvHD according to NIH consesus criteria
  • cumulative incidence of extensive chronic GvHD [ Time Frame: 2 years ]
    cumulative incidence of extensive chronic GvHD according to revised NIH consesus criteria (Jagasia et al. BBMT 2015)
  • cumulative incidence of non-relapse mortality [ Time Frame: 2 years ]
    cumulative incidence of non-relapse mortality, defined as death by any cause in the absence of relapse, as competitive risk versus relapse
  • cumulative incidence of relapse [ Time Frame: 2 years ]
    cumulative incidence of relapse, defined as disease recurrence according to marrow morphology, flow cytometry, cytogenetics, fluorescence in situ hybridization and/or polymerase chain reaction, as competitive risk versus non-relapse mortality
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Irradiation-based Myeloablative Conditioning Followed by Treg/Tcon Immunotherapy in HSCT
Official Title  ICMJE Antileukemic Activity of Allogeneic Hematopoietic Stem Cell Transplantation With Fractionated Total Body Irradiation or Total Marrow and Lymph Node Irradiation Followed by Adoptive Immunotherapy With Regulatory and Conventional T Cells
Brief Summary To evaluate if hyper-fractionated TBI or TMLI followed by Treg/Tcon adoptive immunotherapy improve cGvHD/disease free survival after allogeneic HSCT in patients affected by high-risk acute leukemias or other hematologic malignancy where HSCT is indicated.
Detailed Description Improving cGvHD/disease free survival in patients with high-risk acute leukemias or other hematologic malignancy where HSCT is indicated with the use of a regulatory T cell based protocol. Hyper-fractionated Total Body Irradiation or Total Marrow and Lymphoid Irradiation based conditioning will be followed by the infusion of T regulatory and T conventional cell adoptive immunotherapy and a purified CD34+ hematopoietic stem cell graft. Incidence of Non Relapse Mortality, Relapse, acute Graft versus Host Disease, chronic Graft versus Host Disease, as well as probability of cGvHD/disease free survival will be assessed in patient subpopulations separated according to HLA-matching with the donor (HLA-matched HSCT and HLA-haploidentical HSCT) and type of disease (acute myeloid leukemia, acute lymphoid leukemia, lymphoma, multiple myeloma, myeloproliferative disease, and other).
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Acute Myeloid Leukemia
  • Acute Lymphoid Leukemia
  • Myeloproliferative Disorders
  • Lymphoma
  • Multiple Myeloma
  • Other Hematologic Malignant Neoplasms
Intervention  ICMJE Biological: High dose irradiation conditioning + Treg/Tcon
High dose irradiation based conditioning regimens followed by infusion of donor regulatory and conventional T cells and purified CD34+ hematopoietic stem cell transplantation
Study Arms  ICMJE Experimental: High dose irradiation conditioning + Treg/Tcon
High dose irradiation based conditioning regimens followed by infusion of donor regulatory and conventional T cells and purified CD34+ hematopoietic stem cell transplantation
Intervention: Biological: High dose irradiation conditioning + Treg/Tcon
Publications *
  • Di Ianni M, Falzetti F, Carotti A, Terenzi A, Castellino F, Bonifacio E, Del Papa B, Zei T, Ostini RI, Cecchini D, Aloisi T, Perruccio K, Ruggeri L, Balucani C, Pierini A, Sportoletti P, Aristei C, Falini B, Reisner Y, Velardi A, Aversa F, Martelli MF. Tregs prevent GVHD and promote immune reconstitution in HLA-haploidentical transplantation. Blood. 2011 Apr 7;117(14):3921-8. doi: 10.1182/blood-2010-10-311894. Epub 2011 Feb 3.
  • Martelli MF, Di Ianni M, Ruggeri L, Falzetti F, Carotti A, Terenzi A, Pierini A, Massei MS, Amico L, Urbani E, Del Papa B, Zei T, Iacucci Ostini R, Cecchini D, Tognellini R, Reisner Y, Aversa F, Falini B, Velardi A. HLA-haploidentical transplantation with regulatory and conventional T-cell adoptive immunotherapy prevents acute leukemia relapse. Blood. 2014 Jul 24;124(4):638-44. doi: 10.1182/blood-2014-03-564401. Epub 2014 Jun 12.
  • Pierini A, Ruggeri L, Carotti A, Falzetti F, Saldi S, Terenzi A, Zucchetti C, Ingrosso G, Zei T, Iacucci Ostini R, Piccinelli S, Bonato S, Tricarico S, Mancusi A, Ciardelli S, Limongello R, Merluzzi M, Di Ianni M, Tognellini R, Minelli O, Mecucci C, Martelli MP, Falini B, Martelli MF, Aristei C, Velardi A. Haploidentical age-adapted myeloablative transplant and regulatory and effector T cells for acute myeloid leukemia. Blood Adv. 2021 Mar 9;5(5):1199-1208. doi: 10.1182/bloodadvances.2020003739.

*   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: June 4, 2019) 		80
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE February 28, 2023
Estimated Primary Completion Date February 28, 2023   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • AML and ALL in complete remission and with high-risk of relapse
  • AML and ALL primarily chemoresistant or relapsed;
  • Chronic Myeloid Leukemia in accelerated or blastic phase;

  • Patients affected by

    • Multiple myeloma,
    • Non Hodgkin lymphoma,
    • Hodgkin lymphoma,
    • Chronic myeloproliferative syndrome,
    • Chronic Lymphoid Leukemia,
    • Other Hematological malignancy at high-risk of relapse or detectable disease and where a HSCT is indicated.
  • Age <75 years
  • ECOG ≤ 2
  • Acceptable lung, liver, kidney, and heart function and absence of relevant psichiatric diseases
  • Signature of the informed consent

Exclusion Criteria:

  • Age >75 years
  • ECOG > 2
  • Not acceptable lung, liver, kidney, and heart function and presence of relevant psichiatric diseases
  • Pregnancy
  • No signature of the informed consent
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE up to 75 Years   (Child, Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Antonio Pierini, MD, PhD +390755784147 antonio.pierini@unipg.it
Contact: Mara Merluzzi, MBioTech +393482200239 maramerluzzi@libero.it
Listed Location Countries  ICMJE Italy
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03977103
Other Study ID Numbers  ICMJE 02/14
Has Data Monitoring Committee Not Provided
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 Andrea Velardi, University Of Perugia
Study Sponsor  ICMJE University Of Perugia
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Andrea Velardi, MD, PhD University Of Perugia
PRS Account University Of Perugia
Verification Date January 2020

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

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