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

Official 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

Overview

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.

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.

Interventions

• 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)
• Drug Post-Transplant Cyclophosphamide
  50 mg/kg intravenous 2 days on Day+3/Day+5 after graft (=Day0)
• 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)
• 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)
• Radiation total body irradiation
  2 grays on Day-1 before graft (=Day0)
• Other hematopoietic stem cells
  High dose of hematopoietic stem cells derived from peripheral blood on transplantation day (=Day0 graft)
• 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
• 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)

Primary outcome measures

• 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]

Secondary outcome measures (12)

• Incidence of engraftment [Time frame: Month 1 post-transplant]
• Overall survival (OS) [Time frame: 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]
• GVHD and relapse-free survival (GRFS) [Time frame: 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]
• Incidence of chronic GVHD [Time frame: From month 3 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]
• Incidence of non-relapse mortality (NRM) [Time frame: 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]
• Chimerism [Time frame: At Month1, Month2, Month3, Month6, Month12 post-transplant]
• Immune reconstitution [Time frame: 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]

Eligibility criteria

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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

France · 3 centers

• CHU Angers — Angers
• CHU Brest — Brest
• CHU Nantes — Nantes

Identifiers

NCT: NCT06252870 · RC23_0286

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗