Clinical trial NCT02966301: Treatment of Chronic Graft Versus Host Disease With Arsenic Trioxide
Official title: Phase II Study of First Line Treatment of Chronic Graft Versus Host Disease With Arsenic Trioxide
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Chronic Graft-Versus-Host Disease
Immune System Diseases
Keywords: cGvHD
Arsenic Trioxide
Hematology
Lead sponsor: Medsenic
Sponsor class: INDUSTRY
First posted: 2016-11-17
Enrollment: 21
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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).

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.

Primary outcomes:
measure: Number of Participants With Complete or Partial Remission of Chronic Graft Versus Host Disease After a First Line Treatment With Arsenic Trioxide
timeFrame: six months
Secondary outcomes:
measure: Average Dose of Corticosteroids
timeFrame: Average dose of Prednisone at 6 months after the first infusion of ATO
measure: Failure Free Survival
timeFrame: 6 months after first ATO infusion
measure: Number of Adverse Events
timeFrame: 12 months after the first infusion of ATO for each patient
measure: Cumulative Incidence for Non-relapse Mortality (NRM)
timeFrame: 12 months after first ATO infusion
Other outcomes:
Locations:
Study officials:
affiliation: Hôpital Saint-Antoine, AP-HP - Paris
name: Mohamad Mohty, Pr
role: PRINCIPAL_INVESTIGATOR
affiliation: Institut Universitaire du Cancer - Oncopole - Toulouse
name: Anne Huyhn, Dr
role: PRINCIPAL_INVESTIGATOR
affiliation: Institut d'Hématologie de Basse Normandie - CHU de Caen
name: Sylvain Chantepie, Dr
role: PRINCIPAL_INVESTIGATOR
affiliation: Hôtel Dieu - CHU Nantes
name: Patrice Chevallier, Dr
role: PRINCIPAL_INVESTIGATOR
affiliation: Institut Paoli Calmettes - Centre de Recherche en Cancérologie de Marseille
name: Didier Blaise, Pr
role: PRINCIPAL_INVESTIGATOR
affiliation: Hôpital St Eloi - Montpellier
name: Patrice Ceballos, Dr
role: PRINCIPAL_INVESTIGATOR
affiliation: University Hospital, Limoges
name: Patrice Turlure, Dr
role: PRINCIPAL_INVESTIGATOR
affiliation: University Hospital, Bordeaux
name: Edouard Forcade, Dr
role: PRINCIPAL_INVESTIGATOR
References:
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.