Treatment of Chronic Graft Versus Host Disease With Arsenic Trioxide

Phase 2

Completed

Conditions: Immune System Diseases
Chronic Graft-Versus-Host Disease

Interventions: Drug: Arsenic Trioxide Injectable Solution

Registration Number: NCT02966301

Lead Sponsor: Medsenic

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).

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 21

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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
interventional	Arsenic Trioxide Injectable Solution	Single arm : Arsenic trioxide

Primary Outcome Measures

Name	Time	Method
Number of Participants With Complete or Partial Remission of Chronic Graft Versus Host Disease After a First Line Treatment With Arsenic Trioxide	six months	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

Name	Time	Method
Number of Adverse Events	12 months after the first infusion of ATO for each patient	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)	12 months after first ATO infusion	Non-Relapse Mortality (NRM) of infectious and non-infectious origin
Average Dose of Corticosteroids	Average dose of Prednisone at 6 months after the first infusion of ATO	Average dose in mg/kg/day of prednisone or prednisone equivalent
Failure Free Survival	6 months after first ATO infusion	Treatment failure were defined by: * Initiation of a new systemic treatment for chronic GvHD; * Recurrent or progressive malignancy; * Death