Study Testing Two Conditioning Regimen With a Single Prophylaxis of GVHD by Cyclophosphamide and Methotrexate Post-transplant in Patients Eligible for Matched-donor Allograft Transplantation (CY-MET-RIC)

January 23, 2026 updated by: Nantes University Hospital

Randomized Phase 2 Study Testing Two Conditioning Regimen With a Single Prophylaxis of Graft-versus-host Disease by Cyclophosphamide and Methotrexate Post-transplant in Patients Eligible for Matched-donor Allograft Transplantation

Graft-versus-host disease (GVHD) is a major complication of allogeneic hematopoietic stem cell transplantation (allo-CSH).

Recently, in the context of semi-identical (=haploidentical) HLA donors, but also of compatible HLA donors, the use of cyclophosphamide (CY) administered in high doses at early post-transplant (PT) (=PTCY) (Days +3 and +4 or +5) has shown excellent control of acute and chronic GVH, even enabling the discontinuation of other immunosuppressive drugs administered after allo-CSH (ciclosporin, mycophenolate mofetyl (MMF) or Cellcept).

This step has already been taken in the context of allo-CSH with myeloablative conditioning (MAC), which is a minoritary conditioning in adults.

However, in the context of allo-CSH with reduced-intensity conditioning (RIC), which predominates in adults, this strategy seems insufficient to prevent the risk of GVHD.

The idea of reducing the use of immunosuppressants in the context of RIC/HLA-compatible transplants seems, however, still relevant, in order to reduce their adverse effects, improve patients' quality of life and enhance the reconstitution of the post-transplant immune system.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

For this reason, the investigators now wish to test the administration of a combination of a high dose of early post-transplant CY (PTCY) and methotrexate (MTX) on days (D) D+1, D+4, D+6, D+11 (doses already performed in MAC transplant prophylaxis), with anti-lymphocyte serum (ALS) with RIC conditioning, without ciclosporin or MMF.

The investigators hypothesize that administration of this PTCY+MTX combination will enable immunosuppressive drugs to be discontinued as early as D+11 post-transplant, compared with the usual average of 3 to 4 months.

Study Type

Interventional

Enrollment (Estimated)

82

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Locations

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • Age: ≥ 18 and ≤ 70 years old
  • Patient with hematologic malignancy
  • Indication for HSC allograft with attenuated conditioning
  • Pluripotent stem cell (PSC) engraftment
  • Availability of a 10/10 familial or non-familial HLA compatible donor
  • Consent to the protocol
  • ECOG <=2
  • Woman of childbearing age with negative pregnancy test and on highly effective contraception during treatment and for a period of 12 months after stopping MTX and CY
  • Man of childbearing age with highly effective contraception during treatment and for a period of 6 months after stopping MTX and CY and a period of 12 months after stopping MTX and CY if TBF conditioning regimen arm
  • Negative Hepatitis B, C, HIV serologies
  • Social security affiliation

Exclusion Criteria:

  • History of allograft
  • Patient eligible for myeloablative conditioning (MAC)
  • Bone marrow transplant
  • Other progressive cancerous disease, or antecedent of cancer in the last five years, with the exception of a carcinoma of the skin or a carcinoma in situ of the uterine cole treated and in remission.
  • Progressive psychiatric condition
  • Pregnant or breastfeeding woman,
  • Woman or man of childbearing age with lack of effective contraception
  • Serious and uncontrolled concomitant infection
  • Cardiac: systolic ejection fraction < 50% by transthoracic ultrasound or by isotopic method (isotope gamma angiography), NYHA II, III or IV heart failure, active rhythmic, valvular or ischemic heart disease or anteriority
  • Respiratory with EFR: DLCOc <40% of theoretical
  • Renal: creatinine clearance < 50 ml/min (assessment with MDRD method)
  • Urological: active urinary tract infection, history of acute urothelial toxicity due to cytotoxic chemotherapy or radiotherapy, known obstruction of urinary flow, pre-existing hemorrhagic cystitis
  • Hepatic: transaminases greater than 5 times normal or bilirubin greater than 2 times normal
  • Person protected by law (major under guardianship, curatorship or legal protection)
  • Vaccination against yellow fever in the last year
  • Known or suspected hypersensitivity to rabbit proteins as well as to the active substance and excipients of all investigational and ancillary drugs administered during the study,
  • Contraindication to any of the investigational or adjuvant drugs administered during the study
  • Patient not speaking French

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: (CLO)-BALTIMORE
BALTIMORE conditioning regime for LYMPHOID HEMOPATHY CLO-BALTIMORE conditioning regime for MYELOID HEMOPATHY
Drug: Methotrexate
15 mg/m² on Day+1 after graft (=Day0) 10 mg/m² 3 days on Day+4/Day+6/Day+11 after graft (=Day0)
Other Names:
  • MTX
Drug: Fludarabine
Conditioning regimen: 30 mg/m² Intravenous 5 days from Day-6 to Day-2 (Day-6/Day-5-/Day-4/Day-3/Day-2 before graft (=Day0)
Other Names:
  • Fludarabine Baltimore
Drug: Cycophosphamide
Conditioning regimen: 14.5 mg/kg intravenous 2 days on Day-6/Day-5 before graft (=Day0)
Drug: Anti-Thymoglobulin
Conditioning regimen: 2.5 mg/kg intravenous on Day-2 before graft (=Day0)
Other Names:
  • ATG
Radiation: total body irradiation
2 grays on Day-1 before graft (=Day0)
Other Names:
  • TBI
Other: hematopoietic stem cells
High dose of hematopoietic stem cells derived from peripheral blood on transplantation day (=Day0 graft)
Other Names:
  • HSC
Other: Graft nuclear cells
Graft nuclear cells CD3+ cells if needed after transplantation
Other: Donor Lymphocytes Injection
DLI with CD3+ if relapse after transplantation or in prevention of relapse
Other Names:
  • DLI
Drug: Clofarabine
Conditioning regimen: 30 mg/m² Intravenous 5 days from Day-6 to Day-2 (Day-6/Day-5-/Day-4/Day-3/Day-2 before graft (=Day0)
Drug: Fludarabine
Conditioning regimen: 40 mg/m² intravenous 4 days on Day-5/Day-4/Day-3/Day-2 before graft (=Day0)
Other Names:
  • Fludarabine TBF
Drug: Post-Transplant Cyclophosphamide
50 mg/kg intravenous 2 days on Day+3/Day+5 after graft (=Day0)
Other Names:
  • CY
Active Comparator: TBF
Conditioning regimen for LYMPHOID AND MYELOID HEMOPATHY
Drug: Methotrexate
15 mg/m² on Day+1 after graft (=Day0) 10 mg/m² 3 days on Day+4/Day+6/Day+11 after graft (=Day0)
Other Names:
  • MTX
Drug: Fludarabine
Conditioning regimen: 30 mg/m² Intravenous 5 days from Day-6 to Day-2 (Day-6/Day-5-/Day-4/Day-3/Day-2 before graft (=Day0)
Other Names:
  • Fludarabine Baltimore
Drug: Anti-Thymoglobulin
Conditioning regimen: 2.5 mg/kg intravenous on Day-2 before graft (=Day0)
Other Names:
  • ATG
Other: hematopoietic stem cells
High dose of hematopoietic stem cells derived from peripheral blood on transplantation day (=Day0 graft)
Other Names:
  • HSC
Other: Graft nuclear cells
Graft nuclear cells CD3+ cells if needed after transplantation
Other: Donor Lymphocytes Injection
DLI with CD3+ if relapse after transplantation or in prevention of relapse
Other Names:
  • DLI
Drug: Fludarabine
Conditioning regimen: 40 mg/m² intravenous 4 days on Day-5/Day-4/Day-3/Day-2 before graft (=Day0)
Other Names:
  • Fludarabine TBF
Drug: Thiotepa
Conditioning regimen: 5 mg/kg Intravenous at Day-6 before graft (=Day0)
Drug: Busulfan
Conditioning regimen: 3.2 mg/kg Intravenous 2 days at Day-2 and Day-1 before graft (=Day0)
Drug: Post-Transplant Cyclophosphamide
50 mg/kg intravenous 2 days on Day+3/Day+5 after graft (=Day0)
Other Names:
  • CY

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Incidence of grade 3-4 acute GVHD following allo-CSH for all patients and for each conditioning group (Baltimore and TBF).
Time Frame: Post-transplant through study completion, an average of 1 year
Estimation of the incidence of grade 3 and 4 acute GVHD following allo-CSH (excluding post-DLI* acute GVHD) according to Mount Sinai criteria.
Post-transplant through study completion, an average of 1 year

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Incidence of engraftment
Time Frame: Month 1 post-transplant
Engraftment assessed on hematological reconstitution (number of days of aplasia with PNN <0.5 G/L and platelets < 20 G/L, number of platelet and red cell concentrate transfusions)
Month 1 post-transplant
Overall survival (OS)
Time Frame: Post-transplant through study completion, an average of 1 year
survival between day 0 of transplantation and date of death or last follow-up
Post-transplant through study completion, an average of 1 year
Disease-free survival (DFS)
Time Frame: Post-transplant through study completion, an average of 1 year
survival between day 0 of transplantation and date of relapse, death or last follow-up
Post-transplant through study completion, an average of 1 year
GVHD and relapse-free survival (GRFS)
Time Frame: Post-transplant through study completion, an average of 1 year
relapse-free survival without grade 3-4 acute GVHD or chronic GVHD requiring systemic treatment
Post-transplant through study completion, an average of 1 year
Incidence of acute GVHD grade 2-4
Time Frame: Post-transplant through study completion, an average of 1 year
Acute GVH grade 2-4 according to Mount Sinai criteria
Post-transplant through study completion, an average of 1 year
Incidence of chronic GVHD
Time Frame: From month 3 post-transplant through study completion, an average of 1 year
Chronic GVHD according to NCI criteria
From month 3 post-transplant through study completion, an average of 1 year
Incidence of non-relapse mortality (NRM)
Time Frame: Post-transplant through study completion, an average of 1 year
any death unrelated to relapse or disease progression
Post-transplant through study completion, an average of 1 year
Incidence of relapse
Time Frame: Post-transplant through study completion, an average of 1 year
any documented disease recurrence
Post-transplant through study completion, an average of 1 year
Chimerism
Time Frame: At Month1, Month2, Month3, Month6, Month12 post-transplant
Total donor or mixed chimerism. Total donor chimerism = result >95% donor CD3+ cells. Mixed chimerism = result >5% and <95% donor CD3+ cells.
At Month1, Month2, Month3, Month6, Month12 post-transplant
Immune reconstitution
Time Frame: At Month3, Month6, Month9, Month12 post-transplant
T, NK, B lymphocytes and monocytes
At Month3, Month6, Month9, Month12 post-transplant
Grade 3 and 4 post-transplant adverse events
Time Frame: Post-transplant through study completion, an average of 1 year
Grade 3 and 4 post-transplant adverse events (dates of occurrence) (NCI CTCAE criteria, version number 5)
Post-transplant through study completion, an average of 1 year
Incidence of viral, bacteriological, fungal and parasitic infections
Time Frame: Post-transplant through study completion, an average of 1 year
Infections: viral (CMV, EBV, BKV, adenovirus), bacteriological, fungal and parasitic
Post-transplant through study completion, an average of 1 year
Incidence of corticoresistant acute GVHD
Time Frame: Post-transplant through study completion, an average of 1 year

Acute corticoresistant GVHD according to the criteria of Mohty et al. defined by :

  • worsening/progression of disease after 3 days of 2mg/kg/day systemic corticosteroid therapy with methylprednisolone (or equivalent),
  • non-improvement of disease after 7 days of 2mg/kg/day systemic corticosteroid therapy with methylprednisolone (or equivalent),
  • disease progression to a new organ after treatment with 1mg/kg/day methylprednisolone (or equivalent) in the case of cutaneous or gastrointestinal GVHD or,
  • recurrence of acute GVHD during or after the corticosteroid reduction phase
Post-transplant through study completion, an average of 1 year

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Nantes University Hospital

Investigators

  • Principal Investigator: Sylvain THEPOT, MD, Angers University Hospital
  • Principal Investigator: Marie-Anne COUTURIER, MD, University Hospital, Brest

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

July 18, 2024

Primary Completion (Estimated)

October 18, 2027

Study Completion (Estimated)

July 18, 2028

Study Registration Dates

First Submitted

January 24, 2024

First Submitted That Met QC Criteria

February 1, 2024

First Posted (Actual)

February 12, 2024

Study Record Updates

Last Update Posted (Actual)

January 26, 2026

Last Update Submitted That Met QC Criteria

January 23, 2026

Last Verified

January 1, 2026

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • RC23_0286

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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