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