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Treatment of Chronic Graft Versus Host Disease With Arsenic Trioxide (GvHD-ATO)

Primary Purpose

Chronic Graft-Versus-Host Disease, Immune System Diseases

Status
Completed
Phase
Phase 2
Locations
Study Type
Interventional
Intervention
Arsenic Trioxide Injectable Solution
Sponsored by
Medsenic
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Chronic Graft-Versus-Host Disease focused on measuring cGvHD, Arsenic Trioxide, Hematology

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Adult patients (≥18 years) who have received a first allogeneic stem cell transplantation for a hematological disease (any source of hematopoietic stem cells is authorized; any category of conditioning regimen prior to allo-SCT is authorized; any type of stem cell donors is authorized)
  • Confirmed diagnosis of a first episode of chronic GvHD requiring systemic immunosuppressive therapy (any prior GvHD prophylaxis previously used is accepted). Chronic GvHD diagnosis is defined according to the NIH Working Group Consensus. Chronic GvHD diagnosis will be based on the evaluation of the severity of the different clinical manifestations including:

    • Performance status evaluation
    • Cutaneous evaluation measured by the percentage of extension or the presence of sclerotic features. If relevant, confirmation with a biopsy should be performed whenever possible
    • Oral symptoms
    • Ocular symptoms
    • Gastro-intestinal symptoms
    • Evaluation of liver involvement (total bilirubin, transaminases and alkaline phosphatases)
    • Pulmonary function evaluation
    • Evaluation of the musculoskeletal manifestations, especially the amplitude of the relevant articulations
    • Genital tract symptoms
  • Signed informed consent
  • Absence of contra-indications to the use of ATO
  • Subjects affiliated with an appropriate social security system
  • Men must use a medically acceptable method of contraception throughout the treatment period and for at least 4 months and 10 days following the last treatment administration
  • Women who are of childbearing potential must have a negative serum pregnancy test and agree to use a medically acceptable method of contraception throughout the study and for 3 months following the end of the study
  • Patient not participating or not having participated in a clinical study in the 30 days prior to his/her inclusion in the study

Exclusion Criteria:

  • Patient developing acute GvHD (whether early or "late onset" form)
  • Patients developing overlap GvHD as defined by the 2014 NIH Working Group Consensus (presence of one or more acute GvHD manifestations in a patient with a diagnosis of chronic GvHD)
  • A "mild" form of chronic GvHD not requiring systemic immunosuppressive therapy
  • A "moderate" form of chronic GvHD limited to one organ site not requiring systemic immunosuppressive therapy
  • Patient receiving mycophenolate mofetil
  • Not the first episode of chronic GvHD needing systemic immunosuppressive therapy
  • Second allogeneic stem cell transplant
  • Severe cardiac diseases (congestive heart failure (NYHA class III), recent myocardial infarction (in the past 6 months before the inclusion), histories of unexplained syncope, ...)
  • Significant arrhythmias, electrocardiogram (EKG) abnormalities:
  • Congenital QT syndromes
  • History or presence of significant ventricular or atrial tachyarrhythmia
  • Clinically significant resting bradycardia (< 50 beats per minutes)
  • QTc>450msecformenand>470msecfor women on screening EKG (using the QTcF formula)
  • Right bundle branch block plus left anterior hemiblock, bifascicular block
  • Central or peripheral neuropathy
  • Neutrophils < 0.5 × 109/L
  • Platelets < 50 × 109/L
  • Potassium ≤ 4 mEq/l*
  • Magnesium ≤ 1.8 mg/dl*
  • Calcium ≤ 2.15 mmol/l*
  • Hepatic impairment due to a suspected or proven liver damage, other than direct hepatic cGvHD involvement
  • PT < 50%
  • Renal impairment (creatinine ≥ 100 μmol/l)
  • Uncontrolled systemic infection which in the opinion of the investigator is associated with an increased risk of the patients' death within 1 month after the start of therapy
  • Severe neurological or psychiatric disorders
  • Denied informed consent
  • Pregnancy
  • Women breastfeeding at selection and throughout the treatment period

    • If abnormal at selection, to be corrected and re-validated following electrolytes infusion, before inclusion and each drug perfusion.

Sites / Locations

    Arms of the Study

    Arm 1

    Arm Type

    Experimental

    Arm Label

    interventional

    Arm Description

    Single arm : Arsenic trioxide

    Outcomes

    Primary Outcome Measures

    Number of Participants With Complete or Partial Remission of Chronic Graft Versus Host Disease After a First Line Treatment With Arsenic Trioxide
    Clinical response will be evaluated based on the Working Group Report 2015, published by the National Institute of Health Consensus. Response definition is as follows: Complete remission (CR) is defined as complete disappearance of any sign of chronic GvHD. Partial remission (PR) is defined as a significant improvement as defined by the organ or site specific measurement scale without progression in any other organ or site.

    Secondary Outcome Measures

    Average Dose of Corticosteroids
    Average dose in mg/kg/day of prednisone or prednisone equivalent
    Failure Free Survival
    Treatment failure were defined by: Initiation of a new systemic treatment for chronic GvHD; Recurrent or progressive malignancy; Death
    Number of Adverse Events
    Tolerability and safety of ATO in combination with Prednisone, with or without Ciclosporine, in patients with chronic GvHD after allo-SCT. Adverse events follow-up for all patients throughout the study
    Cumulative Incidence for Non-relapse Mortality (NRM)
    Non-Relapse Mortality (NRM) of infectious and non-infectious origin

    Full Information

    First Posted
    October 28, 2016
    Last Updated
    April 11, 2022
    Sponsor
    Medsenic
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    1. Study Identification

    Unique Protocol Identification Number
    NCT02966301
    Brief Title
    Treatment of Chronic Graft Versus Host Disease With Arsenic Trioxide
    Acronym
    GvHD-ATO
    Official Title
    Phase II Study of First Line Treatment of Chronic Graft Versus Host Disease With Arsenic Trioxide
    Study Type
    Interventional

    2. Study Status

    Record Verification Date
    July 2020
    Overall Recruitment Status
    Completed
    Study Start Date
    December 2016 (Actual)
    Primary Completion Date
    June 2020 (Actual)
    Study Completion Date
    June 2020 (Actual)

    3. Sponsor/Collaborators

    Responsible Party, by Official Title
    Sponsor
    Name of the Sponsor
    Medsenic

    4. Oversight

    Data Monitoring Committee
    Yes

    5. Study Description

    Brief Summary
    This study aims to evaluate the early chronic GvHD events (first line therapy), if the addition of arsenic trioxide to standard therapy with corticosteroids, with or without cyclosporine, will be effective in controlling chronic GvHD and to reduce the duration of corticosteroid therapy
    Detailed Description
    Graft-versus-host disease (GvHD) is the most common long-term complication in patients who underwent allogeneic transplantation. First-line therapy for chronic GVHD is based on immunosuppressive agents (corticosteroids with or without cyclosporine) achieving satisfactory response in around 30% of patients. This is a prospective, national, multicenter, non-randomized Phase II study that will include a total number of 24 patients in which, trioxide d'arsenic will be administrated at 0,15mg/kg/day. Clinical response will be evaluated based on the Working Group Report 2015, published by the National Institute of Health Consensus. Follow-up visits will be weekly for four weeks (ATO cycle), every two weeks from second to third month of ATO treatment, every month from the fourth to sixth month of ATO treatment and every 3 months, at 9 months and 12 months (final visit).

    6. Conditions and Keywords

    Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
    Chronic Graft-Versus-Host Disease, Immune System Diseases
    Keywords
    cGvHD, Arsenic Trioxide, Hematology

    7. Study Design

    Primary Purpose
    Treatment
    Study Phase
    Phase 2
    Interventional Study Model
    Single Group Assignment
    Masking
    None (Open Label)
    Allocation
    N/A
    Enrollment
    21 (Actual)

    8. Arms, Groups, and Interventions

    Arm Title
    interventional
    Arm Type
    Experimental
    Arm Description
    Single arm : Arsenic trioxide
    Intervention Type
    Drug
    Intervention Name(s)
    Arsenic Trioxide Injectable Solution
    Other Intervention Name(s)
    Trisenox / Arscimed
    Intervention Description
    Each patient will receive eleven perfusions of arsenic trioxide (0,15 mg/kg/Day - IV administration) over a 4 weeks period (one cycle). Patients in partial response after the 1st cycle of ATO will be eligible to receive a second cycle of ATO as consolidation therapy. A delay of 8 weeks (from the first infusion of ATO) will be observed between the two cycles of ATO therapy. The study duration will be 2 years (12 months recruitment + 12 months follow-up).
    Primary Outcome Measure Information:
    Title
    Number of Participants With Complete or Partial Remission of Chronic Graft Versus Host Disease After a First Line Treatment With Arsenic Trioxide
    Description
    Clinical response will be evaluated based on the Working Group Report 2015, published by the National Institute of Health Consensus. Response definition is as follows: Complete remission (CR) is defined as complete disappearance of any sign of chronic GvHD. Partial remission (PR) is defined as a significant improvement as defined by the organ or site specific measurement scale without progression in any other organ or site.
    Time Frame
    six months
    Secondary Outcome Measure Information:
    Title
    Average Dose of Corticosteroids
    Description
    Average dose in mg/kg/day of prednisone or prednisone equivalent
    Time Frame
    Average dose of Prednisone at 6 months after the first infusion of ATO
    Title
    Failure Free Survival
    Description
    Treatment failure were defined by: Initiation of a new systemic treatment for chronic GvHD; Recurrent or progressive malignancy; Death
    Time Frame
    6 months after first ATO infusion
    Title
    Number of Adverse Events
    Description
    Tolerability and safety of ATO in combination with Prednisone, with or without Ciclosporine, in patients with chronic GvHD after allo-SCT. Adverse events follow-up for all patients throughout the study
    Time Frame
    12 months after the first infusion of ATO for each patient
    Title
    Cumulative Incidence for Non-relapse Mortality (NRM)
    Description
    Non-Relapse Mortality (NRM) of infectious and non-infectious origin
    Time Frame
    12 months after first ATO infusion

    10. Eligibility

    Sex
    All
    Minimum Age & Unit of Time
    18 Years
    Accepts Healthy Volunteers
    No
    Eligibility Criteria
    Inclusion Criteria: Adult patients (≥18 years) who have received a first allogeneic stem cell transplantation for a hematological disease (any source of hematopoietic stem cells is authorized; any category of conditioning regimen prior to allo-SCT is authorized; any type of stem cell donors is authorized) Confirmed diagnosis of a first episode of chronic GvHD requiring systemic immunosuppressive therapy (any prior GvHD prophylaxis previously used is accepted). Chronic GvHD diagnosis is defined according to the NIH Working Group Consensus. Chronic GvHD diagnosis will be based on the evaluation of the severity of the different clinical manifestations including: Performance status evaluation Cutaneous evaluation measured by the percentage of extension or the presence of sclerotic features. If relevant, confirmation with a biopsy should be performed whenever possible Oral symptoms Ocular symptoms Gastro-intestinal symptoms Evaluation of liver involvement (total bilirubin, transaminases and alkaline phosphatases) Pulmonary function evaluation Evaluation of the musculoskeletal manifestations, especially the amplitude of the relevant articulations Genital tract symptoms Signed informed consent Absence of contra-indications to the use of ATO Subjects affiliated with an appropriate social security system Men must use a medically acceptable method of contraception throughout the treatment period and for at least 4 months and 10 days following the last treatment administration Women who are of childbearing potential must have a negative serum pregnancy test and agree to use a medically acceptable method of contraception throughout the study and for 3 months following the end of the study Patient not participating or not having participated in a clinical study in the 30 days prior to his/her inclusion in the study Exclusion Criteria: Patient developing acute GvHD (whether early or "late onset" form) Patients developing overlap GvHD as defined by the 2014 NIH Working Group Consensus (presence of one or more acute GvHD manifestations in a patient with a diagnosis of chronic GvHD) A "mild" form of chronic GvHD not requiring systemic immunosuppressive therapy A "moderate" form of chronic GvHD limited to one organ site not requiring systemic immunosuppressive therapy Patient receiving mycophenolate mofetil Not the first episode of chronic GvHD needing systemic immunosuppressive therapy Second allogeneic stem cell transplant Severe cardiac diseases (congestive heart failure (NYHA class III), recent myocardial infarction (in the past 6 months before the inclusion), histories of unexplained syncope, ...) Significant arrhythmias, electrocardiogram (EKG) abnormalities: Congenital QT syndromes History or presence of significant ventricular or atrial tachyarrhythmia Clinically significant resting bradycardia (< 50 beats per minutes) QTc>450msecformenand>470msecfor women on screening EKG (using the QTcF formula) Right bundle branch block plus left anterior hemiblock, bifascicular block Central or peripheral neuropathy Neutrophils < 0.5 × 109/L Platelets < 50 × 109/L Potassium ≤ 4 mEq/l* Magnesium ≤ 1.8 mg/dl* Calcium ≤ 2.15 mmol/l* Hepatic impairment due to a suspected or proven liver damage, other than direct hepatic cGvHD involvement PT < 50% Renal impairment (creatinine ≥ 100 μmol/l) Uncontrolled systemic infection which in the opinion of the investigator is associated with an increased risk of the patients' death within 1 month after the start of therapy Severe neurological or psychiatric disorders Denied informed consent Pregnancy Women breastfeeding at selection and throughout the treatment period If abnormal at selection, to be corrected and re-validated following electrolytes infusion, before inclusion and each drug perfusion.
    Overall Study Officials:
    First Name & Middle Initial & Last Name & Degree
    Mohamad Mohty, Pr
    Organizational Affiliation
    Hôpital Saint-Antoine, AP-HP - Paris
    Official's Role
    Principal Investigator
    First Name & Middle Initial & Last Name & Degree
    Anne Huyhn, Dr
    Organizational Affiliation
    Institut Universitaire du Cancer - Oncopole - Toulouse
    Official's Role
    Principal Investigator
    First Name & Middle Initial & Last Name & Degree
    Sylvain Chantepie, Dr
    Organizational Affiliation
    Institut d'Hématologie de Basse Normandie - CHU de Caen
    Official's Role
    Principal Investigator
    First Name & Middle Initial & Last Name & Degree
    Patrice Chevallier, Dr
    Organizational Affiliation
    Hôtel Dieu - CHU Nantes
    Official's Role
    Principal Investigator
    First Name & Middle Initial & Last Name & Degree
    Didier Blaise, Pr
    Organizational Affiliation
    Institut Paoli Calmettes - Centre de Recherche en Cancérologie de Marseille
    Official's Role
    Principal Investigator
    First Name & Middle Initial & Last Name & Degree
    Patrice Ceballos, Dr
    Organizational Affiliation
    Hôpital St Eloi - Montpellier
    Official's Role
    Principal Investigator
    First Name & Middle Initial & Last Name & Degree
    Patrice Turlure, Dr
    Organizational Affiliation
    University Hospital, Limoges
    Official's Role
    Principal Investigator
    First Name & Middle Initial & Last Name & Degree
    Edouard Forcade, Dr
    Organizational Affiliation
    University Hospital, Bordeaux
    Official's Role
    Principal Investigator

    12. IPD Sharing Statement

    Plan to Share IPD
    No
    Citations:
    PubMed Identifier
    35830931
    Citation
    Rongvaux-Gaida D, Dupuis M, Poupon J, Djebrani-Oussedik N, Lemonnier C, Rieger F. High Response Rate and Corticosteroid Sparing with Arsenic Trioxide-Based First-Line Therapy in Chronic Graft-versus-Host Disease after Allogeneic Hematopoietic Stem Cell Transplantation. Transplant Cell Ther. 2022 Oct;28(10):679.e1-679.e11. doi: 10.1016/j.jtct.2022.07.004. Epub 2022 Jul 10.
    Results Reference
    derived

    Learn more about this trial

    Treatment of Chronic Graft Versus Host Disease With Arsenic Trioxide

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