Clinical trial 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
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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Graft Versus Host Disease
Hematologic Malignancy
Keywords: Hematopoietic stem cell allograft (Allo-CSH)
Methotrexate (MTX)
Post-transplant cyclophosphamide (PTCY)
Lead sponsor: Nantes University Hospital
Sponsor class: OTHER
First posted: 2024-02-12
Enrollment: 82
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Multicenter, phase 2, non-comparative, randomized, open-label, prospective drug trial
Primary purpose: TREATMENT

Brief summary: 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.

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

Primary outcomes:
measure: Incidence of grade 3-4 acute GVHD following allo-CSH for all patients and for each conditioning group (Baltimore and TBF).
timeFrame: Post-transplant through study completion, an average of 1 year
Secondary outcomes:
measure: Incidence of engraftment
timeFrame: Month 1 post-transplant
measure: Overall survival (OS)
timeFrame: Post-transplant through study completion, an average of 1 year
measure: Disease-free survival (DFS)
timeFrame: Post-transplant through study completion, an average of 1 year
measure: GVHD and relapse-free survival (GRFS)
timeFrame: Post-transplant through study completion, an average of 1 year
measure: Incidence of acute GVHD grade 2-4
timeFrame: Post-transplant through study completion, an average of 1 year
measure: Incidence of chronic GVHD
timeFrame: From month 3 post-transplant through study completion, an average of 1 year
measure: Incidence of corticoresistant acute GVHD
timeFrame: Post-transplant through study completion, an average of 1 year
measure: Incidence of non-relapse mortality (NRM)
timeFrame: Post-transplant through study completion, an average of 1 year
measure: Incidence of relapse
timeFrame: Post-transplant through study completion, an average of 1 year
measure: Chimerism
timeFrame: At Month1, Month2, Month3, Month6, Month12 post-transplant
measure: Immune reconstitution
timeFrame: At Month3, Month6, Month9, Month12 post-transplant
measure: Grade 3 and 4 post-transplant adverse events
timeFrame: Post-transplant through study completion, an average of 1 year
measure: Incidence of viral, bacteriological, fungal and parasitic infections
timeFrame: Post-transplant through study completion, an average of 1 year
Other outcomes:
Locations:
city: Angers
country: France
facility: CHU Angers
city: Brest
country: France
facility: CHU Brest
city: Nantes
country: France
facility: CHU Nantes
Study officials:
affiliation: Angers University Hospital
name: Sylvain THEPOT, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University Hospital, Brest
name: Marie-Anne COUTURIER, MD
role: PRINCIPAL_INVESTIGATOR
References: