Chronic Graft-Versus-Host Disease, Immune System Diseases
Conditions
Keywords
cGvHD, Arsenic Trioxide, Hematology
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).
Interventions
DRUGArsenic 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).
Sponsors
Medsenic
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 |
| 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 |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Arsenic Trioxide Single arm : Arsenic trioxide
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 8-10 weeks (from the first infusion of ATO) will be observed between the two cycles of ATO therapy.
The study duration was 3.5 years (36 months recruitment + 12 months follow-up). | 21 |
| Total | 21 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Death | 2 |
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Arsenic Trioxide | — |
|---|---|---|
| Age, Continuous | 62 years | — |
| Diagnosis of chronic GvHD requiring systemic immunosuppressive therapy confirmed, | 21 Participants | — |
| Race and Ethnicity Not Collected | — | — Participants |
| Region of Enrollment France | 21 participants | — |
| Sex: Female, Male Female | 11 Participants | — |
| Sex: Female, Male Male | 10 Participants | — |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 2 / 21 |
| other Total, other adverse events | 21 / 21 |
| serious Total, serious adverse events | 21 / 21 |
Outcome results
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.
Time frame: six months
Population: All patients who entered the study, completed their first cycle of ATO and for whom the response at Week 6 after diagnosis of chronic GvHD has been evaluated.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Interventional | Number of Participants With Complete or Partial Remission of Chronic Graft Versus Host Disease After a First Line Treatment With Arsenic Trioxide | 15 Participants |
Secondary
Average Dose of Corticosteroids
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
Population: All patients who entered the study, completed their first cycle of ATO and for whom the response at Week 6 after diagnosis of chronic GvHD has been evaluated.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Interventional | Average Dose of Corticosteroids | 0.22 mg/kg/day | Standard Deviation 0.29 |
Secondary
Cumulative Incidence for Non-relapse Mortality (NRM)
Non-Relapse Mortality (NRM) of infectious and non-infectious origin
Time frame: 12 months after first ATO infusion
Population: FAS
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Interventional | Cumulative Incidence for Non-relapse Mortality (NRM) | 5 percentage of participants |
Secondary
Failure Free Survival
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
Population: FAS
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Interventional | Failure Free Survival | 90 percentage of participants |
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
Time frame: 12 months after the first infusion of ATO for each patient
Population: Safety Analysis Population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Interventional | Number of Adverse Events | 197 number of events |