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| ID | Type | Description | Link |
|---|---|---|---|
| 2017-002691-98 | EudraCT Number |
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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
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Methotrexate | Experimental |
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| Placebo | Placebo Comparator |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Methotrexate | Drug | 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. |
| 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). |
| 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. |
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Inclusion Criteria:
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:
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| Name | Affiliation | Role |
|---|---|---|
| Mohamad Mohty, PU-PH | Assistance Publique - Hôpitaux de Paris | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Saint Antoine Hospital - Hematology Department | Paris | 75012 | France |
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| Placebo | Drug | 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. |
|
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. |
| 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 |
| ID | Term |
|---|---|
| D006086 | Graft vs Host Disease |
| ID | Term |
|---|---|
| D007154 | Immune System Diseases |
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| ID | Term |
|---|---|
| D008727 | Methotrexate |
| ID | Term |
|---|---|
| D000630 | Aminopterin |
| D011622 | Pterins |
| D011621 | Pteridines |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D006571 | Heterocyclic Compounds |
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