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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

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

NCT ID

NCT02966301

First Posted

October 28, 2016

Last Updated

April 11, 2022

Sponsor

Medsenic

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

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

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

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: