Treatment of Chronic Graft Versus Host Disease With Arsenic Trioxide

Immune System Diseases Clinical Trial

— GvHD-ATO  

Official title:

Phase II Study of First Line Treatment of Chronic Graft Versus Host Disease With Arsenic Trioxide

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02966301
• Other study ID #: GMED16-001
• Status: Completed
• Phase: Phase 2
• Start date: December 2016
• Est. completion date: June 2020

Study information

• Verified date: July 2020
• Source: Medsenic
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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

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 information / eligibility

• Status: Completed
• Enrollment: 21
• Est. completion date: June 2020
• Est. primary completion date: June 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Chronic Graft-Versus-Host Disease
• Graft vs Host Disease
• Immune System Diseases

Intervention

Drug:
• Arsenic Trioxide Injectable Solution
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).

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
Medsenic

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.	six months
Secondary	Average Dose of Corticosteroids	Average dose in mg/kg/day of prednisone or prednisone equivalent	Average dose of Prednisone at 6 months after the first infusion of ATO
Secondary	Failure Free Survival	Treatment failure were defined by: Initiation of a new systemic treatment for chronic GvHD; Recurrent or progressive malignancy; Death	6 months after first ATO infusion
Secondary	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	12 months after the first infusion of ATO for each patient
Secondary	Cumulative Incidence for Non-relapse Mortality (NRM)	Non-Relapse Mortality (NRM) of infectious and non-infectious origin	12 months after first ATO infusion