Etude : MTX GvHD /



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Acronyme / Nom
Situation thérapeutique
Traitement
Cadre réglementaire
MÀJ
Présentation de l'étude
Acronyme / Nom : MTX GvHD

Situation thérapeutique : GvH

Traitement :

Cadre réglementaire : RIPH1

Dernière MÀJ : 30/11/2021
Titre
Spécialité(s)
CIM10 - Localisation(s)
Informations principales
Titre : Etude de phase III randomisée, multicentrique, en double-insu comparant le méthotrexate (MTX) à faible dose et le traitement standard dans le traitement de première ligne de la réaction aigue du greffon contre l’hôte après allogreffe de cellules souches hématopoïétiques ((MTX-aGVHD)

Spécialité : Tissus lymphoïde, hématopoïétique et apparentés
Localisation : C96 - Tumeurs malignes des tissus lymphoïde, hématopoïétique et apparentés, autres et non précisées
Schéma
Phase
Stade
Ligne(s)
Informations complémentaires
Schéma : STUDY DESIGN:
This is a phase III randomized, multicenter, double blinded controlled study. Patients who develop clinically meaningful acute GVHD and who meet all other entry criteria will be randomized 1:1 to receive either corticosteroids and placebo ("standard of care", control arm) or the combination of low-dose MTX with corticosteroids as first-line therapy for acute GVHD (MTX; "experimental arm").

The primary analysis of this hypothesis generation study is to estimate the composite endpoint of GVHD-free and corticosteroids-free survival at 12 months after randomization in both treatment arms. In fact, it is more and more established that such composite endpoint is a clinically very relevant one because it represents ideal recovery from allo-SCT (Stem Cell transplantation) (at 1 year after acute GVHD diagnosis) and a measure of cure without ongoing morbidity.

STUDY ARMS:
- Experimental: Methotrexate
5mg/Kg/day methotrexate for 4 weeks then 3 mg/m2 every two weeks for 12 weeks
2mg/kg/day PO prednisone prednisone (or 1.6 mg/kg/day IV methylprednisolone) once daily.
10 mg po or iv lederfolin after each MTX administration

- Placebo Comparator: Placebo
Once a week placebo for 4 weeks then every two weeks for 12 weeks
2 mg/kg/day PO prednisone (or 1.6 mg/kg/day IV methylprednisolone) once daily.
10 mg po or iv lederfolin after each placebo administration

CURRENT PRIMARY OUTCOMES:
Assessment of a composite endpoint of graft-versus-host disease-free at 12 months after randomization.

CURRENT SECONDARY OUTCOMES:
-The incidence of severe adverse events within the first 12 months after randomization [ Time Frame: 12 months after randomization ]
- The proportion of complete remission (CR), very good partial response (VGPR), partial response (PR), mixed response (MR), no response (NR) and progression at day 28, day 56 and best response within the first 12 months after randomization. [ Time Frame: at day 28, day 56 and best response within the first 12 months after randomization. ]
- The proportion of GVHD flare within the first 12 months after randomization. [ Time Frame: 12 months after randomization ]
- Cumulative incidence of overall and severe chronic GVHD as assessed by NIH Consensus Criteria within the first 12 months after randomization(Jagasia, Greinix et al. 2015, Lee, Wolff et al. 2015). [ Time Frame: within the first 12 months after randomization ]
- Incidence of systemic of infection and CMV(cytomegalovirus ) reactivation within 3 months after randomization [ Time Frame: within 3 months after randomization ]
- Incidence of EBV (Epstein-Barr virus) reactivation and post-transplant lymphoproliferative disease within 12 months after randomization [ Time Frame: within 12 months after randomization ]
- Cumulative incidence of non-relapse mortality within the first 12 months after randomization. [ Time Frame: 12 months after randomization ]
- Corticosteroids-free, disease-free and overall survival within the first 12 months after randomization. [ Time Frame: 12 months after randomization ]
Immune recovery and microbiota: number of patients with complete immune recovery (lymphocytes and dendritic cells) and correction of microbiota dysbiosis within the first 12 months [ Time Frame: 12 months after randomization ]
- Quality of Life (QoL)-1 [ Time Frame: 12 Months ]
- Quality of Life (QoL)-2 [ Time Frame: 12 Months ]

Phase : III

Stade : NA

1
Informations issues du synopsis en français (autorisation donnée par le promoteur)
Critères d'inclusion
Critères de non-inclusion
Informations issues du synopsis en français (autorisation donnée par le promoteur)
Critères d'inclusion et de non-inclusion
Critères d'inclusion : - Adults patients (>=18 years old) with hematological diseases, who develop a first episode of acute GVHD (grade II-IV) requiring systemic therapy
- First allo-SCT, with any type of donor, stem cell source, GVHD prophylaxis or conditioning regimen
- Biopsy of acute GVHD target organ is recommended, but not required. Enrollment should not be delayed awaiting biopsy or pathology results
- The patient must have received no previous systemic immune suppressive therapy for treatment of acute GVHD, except for a maximum 72 hours of prior corticosteroid therapy
- Absolute neutrophil count (ANC) greater than 0.5 G/L
- Platelets count greater than 20 G/L
- Signed informed consent
- Affiliation to a social security system (recipient or assign)
- Women who are of childbearing potential must have a negative serum pregnancy test and agree to use a medically acceptable method of contraception until 6 months after the end of treatment.
- Men with a partner of childbearing potential must agree to use a medically acceptable method of contraception until 6 months after the end of treatment.

Critères de non-inclusion : - Hyper-acute GVHD as defined by the MD Anderson's criteria (Saliba, de Lima et al. 2007)
- Flare of GVHD in a patient already on corticosteroid treatment
- Overlap chronic GVHD as defined by the NIH Consensus Criteria (Jagasia, Greinix et al. 2015)
- MTX given within 7 days of enrollment
- Active uncontrolled infection
- Relapsed/persistent malignancy requiring rapid immune suppression withdrawal
- Acute GVHD after donor lymphocytes infusion (DLI)
- Other systemic drugs for GVHD treatment (including extra-corporeal photopheresis)
- If any prior steroid therapy (for indication other than GVHD), treatment at doses > 0.5 mg/kg/day methyl-prednisolone within 7 days prior to onset of acute GVHD
- Patients who are pregnant, breast feeding, or if sexually active, unwilling to use effective birth control for the duration of the study
- Patient on dialysis
- Patients with veno-occlusive disease of the liver or with significant liver abnormalities who in the judgment of the treating physician cannot receive MTX
- Patients requiring after inclusion in the protocol the continuation of one or more of the following medication: probenecide, trimethoprime (alone or in combination with sulfametoxazole), phenylbutazone or yellow fever vaccine
- Patients with a history of intolerance/allergy to MTX
- Hypersensitivity to the active substance or to any of the excipients
NCT
Promoteur
Coordonnateur
Informations relatives au promoteur
NCT :
NCT03371667
Promoteur :
APHP
Type de sponsor : Institutionnel
75010 PARIS 10

Coordonnateur :
Centre investigateur
Investigateur
TEC / ARC / IDE
État
MÀJ
Informations relatives aux investigateurs
Centre investigateur :
Centre Hospitalier Universitaire de Lille - 2 Avenue Oscar Lambret - 59000 LILLE

Investigateur :
Professeur Ibrahim YAKOUB-AGHA

TEC / ARC / IDE :
Secrétariat de recherche
fanny.miquel@
chru-lille.fr
03.20.44.57.13

Statut de l'essai : OUVERT

MAJ : 01/07/2021