search
Back to results

Phase III Study Comparing GVHD Prophylaxis With ATG-thymoglobulin to ATLG-grafalon in Elderly Patients With Acute Myeloid Leukemia or Myelodysplasic Syndrome and Receiving an Allogeneic Hematopoietic Stem Cell Transplantation With a 10/10 HLA Matched Unrelated Donor (OPTISAGE)

Primary Purpose

GVHD

Status
Not yet recruiting
Phase
Phase 3
Locations
Study Type
Interventional
Intervention
Grafalon
Thymoglobulin
Sponsored by
Assistance Publique - Hôpitaux de Paris
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional prevention trial for GVHD

Eligibility Criteria

50 Years - 70 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria: Age ≥ 50 and ≤ 70 years Patient between 50 and 55 years should be unfit for a myeloblative conditioning (SORROR score ≥2) AML requiring allogeneic stem cell transplantation (intermediate or high-risk AML) in complete cytologic response (CR1 or above) or MDS requiring allogeneic stem cell transplantation (IPSS≥ 1.5 or IPSS-R > 4.5 or IPSS-R > 3-4.5 with risk features [rapide blast increase, life-threatening neutropenia (<0.3 G/L) or thrombopenia (<30G/L) or high transfusion needs (>2/month for 6 months)] Without an HLA matched related donor Having an identified matched HLA 10/10 unrelated donor With usual criteria for HSCT: ECOG performans status ≤ 2 No severe and uncontrolled infection Cardiac left ventricular ejection fraction ≥50% Lung DLCO > 40% Adequate organ function: ASAT and ALAT ≤ 3N, total bilirubin ≤ 2N, creatinine clearance ≥ 50 mL/min (except if those abnormalities are linked to the hematological disease) With health insurance coverage Having signed a written informed consent Contraception methods must be prescribed during all the duration of the research NB: The authorized contraceptive methods are: For women of childbearing age and in absence of permanent sterilization: oral, intravaginal or transdermal combined hormonal contraception, oral, injectable or transdermal progestogen-only hormonal contraception, intrauterine hormonal releasing system (IUS), sexual abstinence (only if this the preferred and usual lifestyle of the participants). For man in absence of permanent sterilization: sexual abstinence, condoms Exclusion Criteria: Cancer in the last 5 years (except basal cell carcinoma of the skin or "in situ" carcinoma of the cervix) Uncontrolled infection Seropositivity for HIV or HTLV-1 or active hepatitis B or C Yellow fever vaccine and all others live virus vaccines within 2 months before transplantation Heart failure according to NYHA (II or more) or Left ventricular ejection fraction < 50%. Lung DLCO ≤ 40% Preexisting acute hemorrhagic cystitis Renal failure with creatinine clearance < 50ml / min Pregnancy (β-HCG positive) or breast-feeding Patients with any debilitating medical or psychiatric illness, which would preclude the realization of the SCT or the understanding of the protocol Patient under state medical aid Patient under legal protection (protection of the court, or in curatorship or guardianship). For Grafalon: Hypersensitivity to the active substance or to any of the excipients For Thymoglobulin: Hypersensitivity to rabbit proteins or to any of the excipients Participation in other interventional clinical trials Any contraindication mentioned in the SmPC of all auxiliary medicinal products planned to be used in the trial: cyclosporine, mycophenolate mofetil, fludarabine, treosulfan

Sites / Locations

    Arms of the Study

    Arm 1

    Arm 2

    Arm Type

    Active Comparator

    Active Comparator

    Arm Label

    Anti-T lymphocyte globulin (ATLG)

    Anti Thymocyte Globulins (ATG)

    Arm Description

    Outcomes

    Primary Outcome Measures

    Incidence of grade II-IV acute Graft Versus Host Disease (GVHD) according to the Mount Sinai Acute GVHD International Consortium (MAGIC) classification
    Acute GVHD MAGIC classification permit to diagnose and score the severity of acute GVHD. MAGIC score varies from Grade 0 to Grade 4. The higher the score the more severe the damage.

    Secondary Outcome Measures

    Number of patients with at least 3 consecutive days with neutrophils > 0.5 G/L and platelets > 20 G/L
    Hematopoietic recoveries
    T, B, NK, regulatory T cell and gammaglobulin levels in the peripheral blood
    Immune reconstitution
    T, B, NK, regulatory T cell and gammaglobulin levels in the peripheral blood
    Immune reconstitution
    T, B, NK, regulatory T cell and gammaglobulin levels in the peripheral blood
    Immune reconstitution
    T, B, NK, regulatory T cell and gammaglobulin levels in the peripheral blood
    Immune reconstitution
    T, B, NK, regulatory T cell and gammaglobulin levels in the peripheral blood
    Immune reconstitution
    Percentage of chimerism
    Percentage of chimerism
    Percentage of chimerism
    Percentage of chimerism
    Incidence of grade I acute GVHD
    Treatments for acute GVHD will be described : first line treatment, response to steroids, treatment courses for refractory acute GVHD
    Incidence of chronic GVHD
    Incidence of chronic GVHD according to National Institutes of Health (NIH) classification. The gradation of chronic GvHD is defined by the number and score of affected organ. The higher the score of each organ and the higher the number of organs affected, the more severe the damage.
    Incidence of chronic GVHD
    Incidence of chronic GVHD according to National Institutes of Health (NIH) classification. The gradation of chronic GvHD is defined by the number and score of affected organ. The higher the score of each organ and the higher the number of organs affected, the more severe the damage.
    Incidence of relapse
    Relapse will be defined by the reappearance of leukemic cells or MDS features after allo-HSCT in the bonne marrow (cytology +/- cytogenetic analysis from bone marrow aspiration) or extra-medullary sites (proven by a biopsy).
    Incidence of relapse
    Relapse will be defined by the reappearance of leukemic cells or MDS features after allo-HSCT in the bonne marrow (cytology +/- cytogenetic analysis from bone marrow aspiration) or extra-medullary sites (proven by a biopsy).
    Progression free survival
    Progression free survival
    Number of severe infections
    Severe infections correspond to grade 3-4 according to Common Terminology Criteria for Adverse Events
    Number of severe infections
    Severe infections correspond to grade 3-4 according to Common Terminology Criteria for Adverse Events
    Incidence of CytoMegaloVirus (CMV) reactivation
    Incidence of CytoMegaloVirus (CMV) reactivation
    Incidence of CytoMegaloVirus (CMV) reactivation
    Incidence of Ebstein Barr Virus (EBV) reactivation
    Incidence of Ebstein Barr Virus (EBV) reactivation
    Incidence of Ebstein Barr Virus (EBV) reactivation
    Non-relapse mortality
    Non-relapse mortality
    Non-relapse mortality
    Overall survival
    Overall survival
    GVHD and relapse free survival (GRFS)
    Defined by being alive without disease relapse and without having developed acute grade III-IV or severe chronic GVHD
    Health-related Quality of life
    Assessed by using the FACT-BMT-v4 questionnaire. It is a 50 items score. The score varies between 0 to 200. The higher the score the lower the quality of life.
    Health-related Quality of life
    Assessed by using the FACT-BMT-v4 questionnaire. It is a 50 items score. The score varies between 0 to 200. The higher the score the lower the quality of life.
    Health-related Quality of life
    Assessed by using the FACT-BMT-v4 questionnaire. It is a 50 items score. The score varies between 0 to 200. The higher the score the lower the quality of life.
    Health-related Quality of life
    Assessed by using the FACT-BMT-v4 questionnaire. It is a 50 items score. The score varies between 0 to 200. The higher the score the lower the quality of life.
    Number of days of hospitalization for the transplant and after the hospitalization for transplantation related complications
    Incidence and severity of veino-occlusive disease (VOD)
    Lymphocyte counts on standard blood counts before conditioning
    Number of late acute GvHD, overlap syndromes and chronic GvHD

    Full Information

    First Posted
    October 9, 2023
    Last Updated
    October 9, 2023
    Sponsor
    Assistance Publique - Hôpitaux de Paris
    search

    1. Study Identification

    Unique Protocol Identification Number
    NCT06083129
    Brief Title
    Phase III Study Comparing GVHD Prophylaxis With ATG-thymoglobulin to ATLG-grafalon in Elderly Patients With Acute Myeloid Leukemia or Myelodysplasic Syndrome and Receiving an Allogeneic Hematopoietic Stem Cell Transplantation With a 10/10 HLA Matched Unrelated Donor
    Acronym
    OPTISAGE
    Official Title
    Phase III Study Comparing GVHD Prophylaxis With ATG-thymoglobulin to ATLG-grafalon in Elderly Patients With Acute Myeloid Leukemia or Myelodysplasic Syndrome and Receiving an Allogeneic Hematopoietic Stem Cell Transplantation With a 10/10 HLA Matched Unrelated Donor Following a Reduced Intensity Conditioning Regimen by Fludarabine-treosulfan
    Study Type
    Interventional

    2. Study Status

    Record Verification Date
    July 2023
    Overall Recruitment Status
    Not yet recruiting
    Study Start Date
    November 1, 2023 (Anticipated)
    Primary Completion Date
    February 15, 2027 (Anticipated)
    Study Completion Date
    November 1, 2028 (Anticipated)

    3. Sponsor/Collaborators

    Responsible Party, by Official Title
    Sponsor
    Name of the Sponsor
    Assistance Publique - Hôpitaux de Paris

    4. Oversight

    Studies a U.S. FDA-regulated Drug Product
    No
    Studies a U.S. FDA-regulated Device Product
    No
    Data Monitoring Committee
    Yes

    5. Study Description

    Brief Summary
    Allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains the only curative therapy in acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Most of the patients requiring an allo-HSCT are above 50 years of age and are transplanted with a reduced intensity conditioning (RIC) regimen. The optimal RIC and Graft Versus Host Disease (GVHD) prophylaxis regimen allowing a good control of the disease while preventing GVHD remains to be determined for elderly patients. A phase III trial comparing the conventional RIC fludarabine-busulfan 2 days to fludarabine-treosulfan demonstrated an advantage for the flu-treosulfan arm in terms of event free survival (EFS), that should therefore be considered as the new standard of RIC regimen for AML and MDS. GVHD prevention has a crucial role in post-transplant outcomes by potentially interfering with the graft-versus-leukemia (GVL) effect and immune reconstitution. Anti-thymocyte globulins (ATG) are recommended to reduce the risk of acute and chronic GVHD in transplants performed with matched unrelated donors. However, the optimal type of ATG between the 2 approved brands (ATG-thymoglobulin and ATLG-grafalon) displaying distinct characteristics and the optimal dose of ATG are still unknown. In a retrospective study of patients transplanted mainly with RIC with matched related and unrelated donors for haematological malignancies, we observed that Anti-T lymphocyte globulin (ATLG) was associated with a reduction of grade II-IV acute GVHD in comparison to ATG without increasing the incidence of relapse. In this phase III randomised study, we propose to compare GVHD prevention with ATG versus ATLG in AML and MDS patients above 50 years of age transplanted with a matched unrelated donor following a fludarabine-treosulfan RIC, with the hypothesis that ATLG would better control GVHD in this population of patients thus limiting the risk of morbidity and mortality of the procedure.

    6. Conditions and Keywords

    Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
    GVHD

    7. Study Design

    Primary Purpose
    Prevention
    Study Phase
    Phase 3
    Interventional Study Model
    Parallel Assignment
    Masking
    None (Open Label)
    Allocation
    Randomized
    Enrollment
    324 (Anticipated)

    8. Arms, Groups, and Interventions

    Arm Title
    Anti-T lymphocyte globulin (ATLG)
    Arm Type
    Active Comparator
    Arm Title
    Anti Thymocyte Globulins (ATG)
    Arm Type
    Active Comparator
    Intervention Type
    Drug
    Intervention Name(s)
    Grafalon
    Intervention Description
    10 mg/Kg/day IV for 3 consecutive days (day-3 to -1 before transplantation)
    Intervention Type
    Drug
    Intervention Name(s)
    Thymoglobulin
    Intervention Description
    2.5 mg/Kg/day IV for 2 consecutive days (day-3 and -2 before transplantation)
    Primary Outcome Measure Information:
    Title
    Incidence of grade II-IV acute Graft Versus Host Disease (GVHD) according to the Mount Sinai Acute GVHD International Consortium (MAGIC) classification
    Description
    Acute GVHD MAGIC classification permit to diagnose and score the severity of acute GVHD. MAGIC score varies from Grade 0 to Grade 4. The higher the score the more severe the damage.
    Time Frame
    At day 100 post-transplantation
    Secondary Outcome Measure Information:
    Title
    Number of patients with at least 3 consecutive days with neutrophils > 0.5 G/L and platelets > 20 G/L
    Description
    Hematopoietic recoveries
    Time Frame
    Up to 24 months
    Title
    T, B, NK, regulatory T cell and gammaglobulin levels in the peripheral blood
    Description
    Immune reconstitution
    Time Frame
    1 month after transplantation
    Title
    T, B, NK, regulatory T cell and gammaglobulin levels in the peripheral blood
    Description
    Immune reconstitution
    Time Frame
    100 days after transplantation
    Title
    T, B, NK, regulatory T cell and gammaglobulin levels in the peripheral blood
    Description
    Immune reconstitution
    Time Frame
    6 months after transplantation
    Title
    T, B, NK, regulatory T cell and gammaglobulin levels in the peripheral blood
    Description
    Immune reconstitution
    Time Frame
    12 months after transplantation
    Title
    T, B, NK, regulatory T cell and gammaglobulin levels in the peripheral blood
    Description
    Immune reconstitution
    Time Frame
    24 months after transplantation
    Title
    Percentage of chimerism
    Time Frame
    1 month after transplantation
    Title
    Percentage of chimerism
    Time Frame
    100 days after transplantation
    Title
    Percentage of chimerism
    Time Frame
    6 months after transplantation
    Title
    Percentage of chimerism
    Time Frame
    12 months after transplantation
    Title
    Incidence of grade I acute GVHD
    Description
    Treatments for acute GVHD will be described : first line treatment, response to steroids, treatment courses for refractory acute GVHD
    Time Frame
    Up to 24 months
    Title
    Incidence of chronic GVHD
    Description
    Incidence of chronic GVHD according to National Institutes of Health (NIH) classification. The gradation of chronic GvHD is defined by the number and score of affected organ. The higher the score of each organ and the higher the number of organs affected, the more severe the damage.
    Time Frame
    12 months after transplantation
    Title
    Incidence of chronic GVHD
    Description
    Incidence of chronic GVHD according to National Institutes of Health (NIH) classification. The gradation of chronic GvHD is defined by the number and score of affected organ. The higher the score of each organ and the higher the number of organs affected, the more severe the damage.
    Time Frame
    24 months after transplantation
    Title
    Incidence of relapse
    Description
    Relapse will be defined by the reappearance of leukemic cells or MDS features after allo-HSCT in the bonne marrow (cytology +/- cytogenetic analysis from bone marrow aspiration) or extra-medullary sites (proven by a biopsy).
    Time Frame
    12 months after transplantation
    Title
    Incidence of relapse
    Description
    Relapse will be defined by the reappearance of leukemic cells or MDS features after allo-HSCT in the bonne marrow (cytology +/- cytogenetic analysis from bone marrow aspiration) or extra-medullary sites (proven by a biopsy).
    Time Frame
    24 months after transplantation
    Title
    Progression free survival
    Time Frame
    12 months after transplantation
    Title
    Progression free survival
    Time Frame
    24 months after transplantation
    Title
    Number of severe infections
    Description
    Severe infections correspond to grade 3-4 according to Common Terminology Criteria for Adverse Events
    Time Frame
    100 days after transplantation
    Title
    Number of severe infections
    Description
    Severe infections correspond to grade 3-4 according to Common Terminology Criteria for Adverse Events
    Time Frame
    12 months after transplantation
    Title
    Incidence of CytoMegaloVirus (CMV) reactivation
    Time Frame
    100 days after transplantation
    Title
    Incidence of CytoMegaloVirus (CMV) reactivation
    Time Frame
    6 months after transplantation
    Title
    Incidence of CytoMegaloVirus (CMV) reactivation
    Time Frame
    12 months after transplantation
    Title
    Incidence of Ebstein Barr Virus (EBV) reactivation
    Time Frame
    100 days after transplantation
    Title
    Incidence of Ebstein Barr Virus (EBV) reactivation
    Time Frame
    6 months after transplantation
    Title
    Incidence of Ebstein Barr Virus (EBV) reactivation
    Time Frame
    12 months after transplantation
    Title
    Non-relapse mortality
    Time Frame
    6 months after transplantation
    Title
    Non-relapse mortality
    Time Frame
    12 months after transplantation
    Title
    Non-relapse mortality
    Time Frame
    24 months after transplantation
    Title
    Overall survival
    Time Frame
    12 months after transplantation
    Title
    Overall survival
    Time Frame
    24 months after transplantation
    Title
    GVHD and relapse free survival (GRFS)
    Description
    Defined by being alive without disease relapse and without having developed acute grade III-IV or severe chronic GVHD
    Time Frame
    Up to 24 months after transplantation
    Title
    Health-related Quality of life
    Description
    Assessed by using the FACT-BMT-v4 questionnaire. It is a 50 items score. The score varies between 0 to 200. The higher the score the lower the quality of life.
    Time Frame
    At inclusion
    Title
    Health-related Quality of life
    Description
    Assessed by using the FACT-BMT-v4 questionnaire. It is a 50 items score. The score varies between 0 to 200. The higher the score the lower the quality of life.
    Time Frame
    100 days after transplantation
    Title
    Health-related Quality of life
    Description
    Assessed by using the FACT-BMT-v4 questionnaire. It is a 50 items score. The score varies between 0 to 200. The higher the score the lower the quality of life.
    Time Frame
    6 months after transplantation
    Title
    Health-related Quality of life
    Description
    Assessed by using the FACT-BMT-v4 questionnaire. It is a 50 items score. The score varies between 0 to 200. The higher the score the lower the quality of life.
    Time Frame
    12 months after transplantation
    Title
    Number of days of hospitalization for the transplant and after the hospitalization for transplantation related complications
    Time Frame
    Up to 12 months after transplantation
    Title
    Incidence and severity of veino-occlusive disease (VOD)
    Time Frame
    100 days after transplantation
    Title
    Lymphocyte counts on standard blood counts before conditioning
    Time Frame
    7 days before transplantation
    Title
    Number of late acute GvHD, overlap syndromes and chronic GvHD
    Time Frame
    from day 100 to day 120 after transplantation

    10. Eligibility

    Sex
    All
    Minimum Age & Unit of Time
    50 Years
    Maximum Age & Unit of Time
    70 Years
    Accepts Healthy Volunteers
    No
    Eligibility Criteria
    Inclusion Criteria: Age ≥ 50 and ≤ 70 years Patient between 50 and 55 years should be unfit for a myeloblative conditioning (SORROR score ≥2) AML requiring allogeneic stem cell transplantation (intermediate or high-risk AML) in complete cytologic response (CR1 or above) or MDS requiring allogeneic stem cell transplantation (IPSS≥ 1.5 or IPSS-R > 4.5 or IPSS-R > 3-4.5 with risk features [rapide blast increase, life-threatening neutropenia (<0.3 G/L) or thrombopenia (<30G/L) or high transfusion needs (>2/month for 6 months)] Without an HLA matched related donor Having an identified matched HLA 10/10 unrelated donor With usual criteria for HSCT: ECOG performans status ≤ 2 No severe and uncontrolled infection Cardiac left ventricular ejection fraction ≥50% Lung DLCO > 40% Adequate organ function: ASAT and ALAT ≤ 3N, total bilirubin ≤ 2N, creatinine clearance ≥ 50 mL/min (except if those abnormalities are linked to the hematological disease) With health insurance coverage Having signed a written informed consent Contraception methods must be prescribed during all the duration of the research NB: The authorized contraceptive methods are: For women of childbearing age and in absence of permanent sterilization: oral, intravaginal or transdermal combined hormonal contraception, oral, injectable or transdermal progestogen-only hormonal contraception, intrauterine hormonal releasing system (IUS), sexual abstinence (only if this the preferred and usual lifestyle of the participants). For man in absence of permanent sterilization: sexual abstinence, condoms Exclusion Criteria: Cancer in the last 5 years (except basal cell carcinoma of the skin or "in situ" carcinoma of the cervix) Uncontrolled infection Seropositivity for HIV or HTLV-1 or active hepatitis B or C Yellow fever vaccine and all others live virus vaccines within 2 months before transplantation Heart failure according to NYHA (II or more) or Left ventricular ejection fraction < 50%. Lung DLCO ≤ 40% Preexisting acute hemorrhagic cystitis Renal failure with creatinine clearance < 50ml / min Pregnancy (β-HCG positive) or breast-feeding Patients with any debilitating medical or psychiatric illness, which would preclude the realization of the SCT or the understanding of the protocol Patient under state medical aid Patient under legal protection (protection of the court, or in curatorship or guardianship). For Grafalon: Hypersensitivity to the active substance or to any of the excipients For Thymoglobulin: Hypersensitivity to rabbit proteins or to any of the excipients Participation in other interventional clinical trials Any contraindication mentioned in the SmPC of all auxiliary medicinal products planned to be used in the trial: cyclosporine, mycophenolate mofetil, fludarabine, treosulfan
    Central Contact Person:
    First Name & Middle Initial & Last Name or Official Title & Degree
    Régis Peffault de Latour, Pr
    Phone
    +33142385073
    Email
    regis.peffaultdelatour@aphp.fr
    First Name & Middle Initial & Last Name or Official Title & Degree
    Jérôme Lambert, Dr
    Phone
    +33142499742
    Email
    jerome.lambert@u-paris.fr

    12. IPD Sharing Statement

    Plan to Share IPD
    Undecided

    Learn more about this trial

    Phase III Study Comparing GVHD Prophylaxis With ATG-thymoglobulin to ATLG-grafalon in Elderly Patients With Acute Myeloid Leukemia or Myelodysplasic Syndrome and Receiving an Allogeneic Hematopoietic Stem Cell Transplantation With a 10/10 HLA Matched Unrelated Donor

    We'll reach out to this number within 24 hrs