Treatment of Chronic Graft Versus Host Disease With Arsenic Trioxide (GvHD-ATO)

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

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

Study Overview

• Status: Completed
• Conditions: Immune System Diseases; Chronic Graft-Versus-Host Disease
• Intervention / Treatment: Drug: Arsenic Trioxide Injectable Solution

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).

• Study Type: Interventional
• Enrollment (Actual): 21
• Phase: Phase 2

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: interventional; Single arm : Arsenic trioxide

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).; Other Names: Trisenox / Arscimed

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
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
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
Cumulative Incidence for Non-relapse Mortality (NRM)	Non-Relapse Mortality (NRM) of infectious and non-infectious origin	12 months after first ATO infusion

Collaborators and Investigators

• Sponsor: Medsenic
• Investigators: Principal Investigator: Mohamad Mohty, Pr, Hôpital Saint-Antoine, AP-HP - Paris; Principal Investigator: Anne Huyhn, Dr, Institut Universitaire du Cancer - Oncopole - Toulouse; Principal Investigator: Sylvain Chantepie, Dr, Institut d'Hématologie de Basse Normandie - CHU de Caen; Principal Investigator: Patrice Chevallier, Dr, Hotel Dieu - CHU Nantes; Principal Investigator: Didier Blaise, Pr, Institut Paoli Calmettes - Centre de Recherche en Cancérologie de Marseille; Principal Investigator: Patrice Ceballos, Dr, Hôpital St Eloi - Montpellier; Principal Investigator: Patrice Turlure, Dr, University Hospital, Limoges; Principal Investigator: Edouard Forcade, Dr, University Hospital, Bordeaux

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): December 1, 2016
• Primary Completion (Actual): June 1, 2020
• Study Completion (Actual): June 1, 2020

Study Registration Dates

• First Submitted: October 28, 2016
• First Submitted That Met QC Criteria: November 14, 2016
• First Posted (Estimate): November 17, 2016

Study Record Updates

• Last Update Posted (Actual): May 9, 2022
• Last Update Submitted That Met QC Criteria: April 11, 2022
• Last Verified: July 1, 2020

More Information

Terms related to this study

• Keywords: Arsenic Trioxide; Hematology; cGvHD
• Additional Relevant MeSH Terms: Immune System Diseases; Graft vs Host Disease; Antineoplastic Agents; Arsenic Trioxide
• Other Study ID Numbers: GMED16-001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No