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 Clinical Trial

— CY-MET-RIC  

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

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT06252870
• Other study ID #: RC23_0286
• Status: Not yet recruiting
• Phase: Phase 2
• Start date: May 15, 2024
• Est. completion date: May 15, 2028

Study information

• Verified date: April 2024
• Source: Nantes University Hospital
• Contact: Amandine LE BOURGEOIS, MD
• Phone: 02 40 08 32 71
• Email: amandine.lebourgeois[@]chu-nantes.fr
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 82
• Est. completion date: May 15, 2028
• Est. primary completion date: September 15, 2027
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 70 Years

Eligibility

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

Related Conditions & MeSH terms

• Graft Versus Host Disease
• Graft vs Host Disease
• Hematologic Malignancy
• Hematologic Neoplasms

Intervention

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)
• Post-Transplant Cyclophosphamide
50 mg/kg intravenous 2 days on Day+3/Day+5 after graft (=Day0)
• 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)
• Cycophosphamide
Conditioning regimen: 14.5 mg/kg intravenous 2 days on Day-6/Day-5 before graft (=Day0)
• 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)
• Graft nuclear cells
Graft nuclear cells CD3+ cells if needed after transplantation
• 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)
• Thiotepa
Conditioning regimen: 5 mg/kg Intravenous at Day-6 before graft (=Day0)
• Busulfan
Conditioning regimen: 3.2 mg/kg Intravenous 2 days at Day-2 and Day-1 before graft (=Day0)
• Fludarabine
Conditioning regimen: 40 mg/m² intravenous 4 days on Day-5/Day-4/Day-3/Day-2 before graft (=Day0)

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
Nantes University Hospital

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Incidence of grade 3-4 acute GVHD following allo-CSH for all patients and for each conditioning group (Baltimore and TBF).	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	Incidence of engraftment	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
Secondary	Overall survival (OS)	survival between day 0 of transplantation and date of death or last follow-up	Post-transplant through study completion, an average of 1 year
Secondary	Disease-free survival (DFS)	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
Secondary	GVHD and relapse-free survival (GRFS)	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
Secondary	Incidence of acute GVHD grade 2-4	Acute GVH grade 2-4 according to Mount Sinai criteria	Post-transplant through study completion, an average of 1 year
Secondary	Incidence of chronic GVHD	Chronic GVHD according to NCI criteria	From month 3 post-transplant through study completion, an average of 1 year
Secondary	Incidence of corticoresistant acute GVHD	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
Secondary	Incidence of non-relapse mortality (NRM)	any death unrelated to relapse or disease progression	Post-transplant through study completion, an average of 1 year
Secondary	Incidence of relapse	any documented disease recurrence	Post-transplant through study completion, an average of 1 year
Secondary	Chimerism	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
Secondary	Immune reconstitution	T, NK, B lymphocytes and monocytes	At Month3, Month6, Month9, Month12 post-transplant
Secondary	Grade 3 and 4 post-transplant adverse events	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
Secondary	Incidence of viral, bacteriological, fungal and parasitic infections	Infections: viral (CMV, EBV, BKV, adenovirus), bacteriological, fungal and parasitic	Post-transplant through study completion, an average of 1 year