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NCT Number: NCT06252870

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

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.

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Key information

Conditions

Graft Versus Host Disease Graft vs Host Disease Hematologic Diseases Hematologic Malignancy Hematologic Neoplasms Hemic and Lymphatic Diseases Immune System Diseases Neoplasms Neoplasms by Site

Age range

18 year–70 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 2

Primary location

CHU Angers, Angers, France

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About this study

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.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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

Treatment and study plan

methotrexate

Drug

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

Post-transplant Cyclophosphamide

Drug

50 mg/kg intravenous 2 days on Day+3/Day+5 after graft (=Day0)

Other names: CY

Fludarabine

Drug

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

Cycophosphamide

Drug

Conditioning regimen: 14.5 mg/kg intravenous 2 days on Day-6/Day-5 before graft (=Day0)

Anti-Thymoglobulin

Drug

Conditioning regimen: 2.5 mg/kg intravenous on Day-2 before graft (=Day0)

Other names: ATG

Total Body Irradiation

Radiation

2 grays on Day-1 before graft (=Day0)

Other names: TBI

hematopoietic stem cells

Other

High dose of hematopoietic stem cells derived from peripheral blood on transplantation day (=Day0 graft)

Other names: HSC

Graft nuclear cells

Other

Graft nuclear cells CD3+ cells if needed after transplantation

Donor Lymphocytes Injection

Other

DLI with CD3+ if relapse after transplantation or in prevention of relapse

Other names: DLI

Clofarabine

Drug

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)

Thiotepa

Drug

Conditioning regimen: 5 mg/kg Intravenous at Day-6 before graft (=Day0)

busulfan

Drug

Conditioning regimen: 3.2 mg/kg Intravenous 2 days at Day-2 and Day-1 before graft (=Day0)

Primary outcomes

  1. 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.

Secondary outcomes

  1. 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)

  2. 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

  3. 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

  4. 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

  5. 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

  6. 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

  7. 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

  8. 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

  9. Incidence of relapse

    Time frame: Post-transplant through study completion, an average of 1 year

    any documented disease recurrence

  10. 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.

  11. Immune reconstitution

    Time frame: At Month3, Month6, Month9, Month12 post-transplant

    T, NK, B lymphocytes and monocytes

  12. 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)

  13. 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

Study contacts

Contact information is provided by the study sponsor or research team.

Amandine LE BOURGEOIS, MD

CONTACT

[email protected]

02 40 08 32 71 ext. +33

Sponsors and collaborators

Lead sponsor

Nantes University Hospital

Other

Registry information

Official study title

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

Acronym: CY-MET-RIC

Important dates

Study start
2024
Primary completion
2027
Study completion
2028
First posted
Feb 12, 2024
Registry last updated
Jan 26, 2026

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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