To Compare the Efficacy of the Addition of Methotrexate (MTX) to Current Standard Acute Graft-versus-host Disease (GVHD) First-line Treatment With Corticosteroids (MTX-aGVHD)

A Multi-center Randomized in Double-blinded Phase III Study Comparing Standard Care Therapy Alone Versus Corticosteroids and Low-dose Methotrexate (MTX) for the First-line Treatment of Acute Graft-versus-host Disease After Allogeneic Stem Cell Transplantation

Phase III randomized double-blinded trial designed to compare the efficacy of the addition of MTX to current standard acute GVHD first-line treatment with corticosteroids. The protocol will use a novel endpoint for benchmarking interventions based on a composite primary endpoint of GVHD-free and corticosteroids-free survival.

The primary endpoint of the trial will be the assessment of a composite endpoint of graft-versus-host disease-free and corticosteroids-free survival at 12 months after randomization

Study Overview

• Status: Active, not recruiting
• Conditions: Stem Cell Transplant Complications; GVHD, Acute; GVH - Graft Versus Host Reaction; Allogeneic Disease
• Intervention / Treatment: Drug: Methotrexate; Drug: Placebo

Detailed Description

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 Type: Interventional
• Enrollment (Actual): 102
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: mohamad Mohty, PU-PH; Phone Number: 01.49.28.26.20; Email: mohamad.mohty@inserm.fr
• Study Contact Backup: Name: Florent Malard, CCU-AH; Phone Number: 01.49.28.26.20; Email: malardf@yahoo.fr

Study Locations

• France
  • Paris, France, 75012
    • Saint Antoine Hospital - Hematology Department

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• 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.

Exclusion Criteria:

• 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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	Drug: Methotrexate; Methotrexate 5 mg/m2 will be given once week for 4 weeks, then 3 mg/m2 every two weeks for 12 weeks. Body surface area will be capped at 2 m2. Methotrexate will be given as an IV infusion over 15 minutes. All patients will received prednisone 2 mg/kg.day PO (or methylprednisolone 1.6 mg/Kg/day) for 3 days. For responding patients between day 4 and 28, the dose of prednisone must be at least 0.25 mg/kg/day prednisone (or 0.2 mg/kg/day methylprednisolone). All patients should receive a folinic acid supplementation 24 hours after each MTX/placebo administration. Lederfoldin 10 mg po or iv will be administered on days 2, 9, 16 and 23. Lederfoldin 10 mg po or iv will be administered on days 37, 51, 65, 79, 93 and 103.
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	Drug: Placebo; Placebo 5 mg/m2 will be given once week for 4 weeks, then 3 mg/m2 every two weeks for 12 weeks. Body surface area will be capped at 2 m2. Placebo will be given as an IV infusion over 15 minutes. All patients will received prednisone 2 mg/kg.day PO (or methylprednisolone 1.6 mg/Kg/day) for 3 days. For responding patients between day 4 and 28, the dose of prednisone must be at least 0.25 mg/kg/day prednisone (or 0.2 mg/kg/day methylprednisolone). All patients should receive a folinic acid supplementation 24 hours after each MTX/placebo administration. Lederfoldin 10 mg po or iv will be administered on days 2, 9, 16 and 23. Lederfoldin 10 mg po or iv will be administered on days 37, 51, 65, 79, 93 and 103.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Assessment of a composite endpoint of graft-versus-host disease-free at 12 months after randomization.	GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day.	Evaluation will be performed at time of inclusion
Assessment of a composite endpoint of graft-versus-host disease-free at 12 months after randomization (1).	GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day.	Evaluation will be performed before start of MTX at the randomization.
Assessment of a composite endpoint of graft-versus-host disease-free at 12 months after randomization (2).	GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day.	Evaluation will be performed at Day 8
Assessment of a composite endpoint of graft-versus-host disease-free at 12 months after randomization (3).	GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day.	Evaluation will be performed at Day 15
Assessment of a composite endpoint of graft-versus-host disease-free at 12 months after randomization (4).	GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day.	Evaluation will be performed at Day 22
Assessment of a composite endpoint of graft-versus-host disease-free at 12 months after randomization (5).	GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day.	Evaluation will be performed at Day 28
Assessment of a composite endpoint of graft-versus-host disease-free at 12 months after randomization (6).	GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day.	Evaluation will be performed at Day 36
Assessment of a composite endpoint of graft-versus-host disease-free at 12 months after randomization (7).	GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day.	Evaluation will be performed at Day 50
Assessment of a composite endpoint of graft-versus-host disease-free at 12 months after randomization (8).	GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day.	Evaluation will be performed at Day 56
Assessment of a composite endpoint of graft-versus-host disease-free at 12 months after randomization (9).	GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day.	Evaluation will be performed at Day 64
Assessment of a composite endpoint of graft-versus-host disease-free at 12 months after randomization (10)	GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day.	Evaluation will be performed at Day 78
Assessment of a composite endpoint of graft-versus-host disease-free at 12 months after randomization (11).	GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day.	Evaluation will be performed at Day 92
Assessment of a composite endpoint of graft-versus-host disease-free at 12 months after randomization (12).	GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day.	Evaluation will be performed at Day 102
Assessment of a composite endpoint of graft-versus-host disease-free at 12 months after randomization (13).	GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day.	Evaluation will be performed at 5 months after randomization.
Assessment of a composite endpoint of graft-versus-host disease-free at 12 months after randomization (14).	GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day.	Evaluation will be performed at 6 months after randomization.
Assessment of a composite endpoint of graft-versus-host disease-free at 12 months after randomization (17).	GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day.	Evaluation will be performed at 9 months after randomization .
Assessment of a composite endpoint of graft-versus-host disease-free at 12 months after randomization (18).	GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day.	Evaluation will be performed at 12 months after randomization.
Assessment of a composite endpoint of corticosteroids-free survival at 12 months after randomization (19).	GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day.	Evaluation will be performed at time of inclusion.
Assessment of a composite endpoint of corticosteroids-free survival at 12 months after randomization (20).	GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day.	Evaluation will be performed before start of MTX at the randomization.
Assessment of a composite endpoint of corticosteroids-free survival at 12 months after randomization (21).	GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day.	Evaluation will be performed at Day 8.
Assessment of a composite endpoint of corticosteroids-free survival at 12 months after randomization (20).	GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day.	Evaluation will be performed at Day 15.
Assessment of a composite endpoint of corticosteroids-free survival at 12 months after randomization (21).	GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day.	Evaluation will be performed at Day 22.
Assessment of a composite endpoint of corticosteroids-free survival at 12 months after randomization (22).	GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day.	Evaluation will be performed at Day 28.
Assessment of a composite endpoint of corticosteroids-free survival at 12 months after randomization (23).	GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day.	Evaluation will be performed at Day 36
Assessment of a composite endpoint of corticosteroids-free survival at 12 months after randomization (24).	GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day.	Evaluation will be performed at Day 50.
Assessment of a composite endpoint of corticosteroids-free survival at 12 months after randomization (25).	GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day.	Evaluation will be performed at Day 56.
Assessment of a composite endpoint of corticosteroids-free survival at 12 months after randomization (26).	GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day.	Evaluation will be performed at Day 64.
Assessment of a composite endpoint of corticosteroids-free survival at 12 months after randomization (27).	GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day.	Evaluation will be performed at Day 78.
Assessment of a composite endpoint of corticosteroids-free survival at 12 months after randomization (28).	GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day.	Evaluation will be performed at D92.
Assessment of a composite endpoint of corticosteroids-free survival at 12 months after randomization (29).	GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day.	Evaluation will be performed at Day 102.
Assessment of a composite endpoint of corticosteroids-free survival at 12 months after randomization (30).	GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day.	Evaluation will be performed at 5 months after randomization.
Assessment of a composite endpoint of corticosteroids-free survival at 12 months after randomization (31).	GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day.	Evaluation will be performed at 6 months after randomization.
Assessment of a composite endpoint of corticosteroids-free survival at 12 months after randomization (32).	GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day.	Evaluation will be performed at 9 months after randomization.
Assessment of a composite endpoint of corticosteroids-free survival at 12 months after randomization (33).	GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day.	Evaluation will be performed at 12 months after randomization.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The incidence of severe adverse events within the first 12 months after randomization		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.		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.		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).		within the first 12 months after randomization
Incidence of systemic of infection and CMV(cytomegalovirus ) reactivation within 3 months after randomization		within 3 months after randomization
Incidence of EBV (Epstein-Barr virus) reactivation and post-transplant lymphoproliferative disease within 12 months after randomization		within 12 months after randomization
Cumulative incidence of non-relapse mortality within the first 12 months after randomization.		12 months after randomization
Corticosteroids-free, disease-free and overall survival within the first 12 months after randomization.		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		12 months after randomization
Quality of Life (QoL)-1	Evaluation by 1 questionnaire: EORTC QLQ-C30 (quality of life questionnaire) (European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30)	12 Months
Quality of Life (QoL)-2	Evaluation by 1 questionnaire: FACT-BMT (Functional Assessment of Cancer Therapy - Bone Marrow Transplant)	12 Months

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris
• Investigators: Principal Investigator: Mohamad Mohty, PU-PH, Assistance Publique - Hôpitaux de Paris

Study record dates

Study Major Dates

• Study Start (Actual): August 16, 2018
• Primary Completion (Estimated): December 1, 2024
• Study Completion (Estimated): December 1, 2024

Study Registration Dates

• First Submitted: July 31, 2017
• First Submitted That Met QC Criteria: December 12, 2017
• First Posted (Actual): December 13, 2017

Study Record Updates

• Last Update Posted (Estimated): January 19, 2024
• Last Update Submitted That Met QC Criteria: January 18, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: Methotrexate; Hematopoietic Stem Cell; Acute GVHD; Corticosteroids therapy; Allogenic stem cell transplantation
• Additional Relevant MeSH Terms: Immune System Diseases; Graft vs Host Disease; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Dermatologic Agents; Reproductive Control Agents; Abortifacient Agents, Nonsteroidal; Abortifacient Agents; Folic Acid Antagonists; Methotrexate
• Other Study ID Numbers: PHRC-K 16-150; 2017-002691-98 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No