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

Phase 2

Recruiting

• Conditions: Hematologic Malignancy; Graft Versus Host Disease
• Interventions: Drug: Methotrexate; Drug: Post-Transplant Cyclophosphamide; Drug: Fludarabine; Drug: Cycophosphamide; Drug: Anti-Thymoglobulin; Other: Donor Lymphocytes Injection; Radiation: total body irradiation; Other: hematopoietic stem cells; Drug: Thiotepa; Other: Graft nuclear cells; Drug: Busulfan; Drug: Clofarabine

• Registration Number: NCT06252870
• Lead Sponsor: Nantes University Hospital

Brief Summary

Graft-versus-host disease (GVHD) is a major complication of allogeneic hematopoietic stem cell transplantation (allo-CSH).
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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.
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Basic Information
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Recruitment & Eligibility
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Study & Design
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Trial Locations

Study Timeline

• Study First Submitted: 2024-01-24
• Study First Submitted QC: 2024-02-01
• Study First Posted: 2024-02-12
• Study Start: 2024-07-18
• Status Verified: 2024-10
• Last Update Submitted: 2024-10-24
• Last Update Posted: 2024-10-28
• Primary Completion: 2027-10-18
• Study Completion: 2028-07-18

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 82

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

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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

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
(CLO)-BALTIMORE	Anti-Thymoglobulin	BALTIMORE conditioning regime for LYMPHOID HEMOPATHY CLO-BALTIMORE conditioning regime for MYELOID HEMOPATHY
(CLO)-BALTIMORE	hematopoietic stem cells	BALTIMORE conditioning regime for LYMPHOID HEMOPATHY CLO-BALTIMORE conditioning regime for MYELOID HEMOPATHY
(CLO)-BALTIMORE	Methotrexate	BALTIMORE conditioning regime for LYMPHOID HEMOPATHY CLO-BALTIMORE conditioning regime for MYELOID HEMOPATHY
(CLO)-BALTIMORE	Post-Transplant Cyclophosphamide	BALTIMORE conditioning regime for LYMPHOID HEMOPATHY CLO-BALTIMORE conditioning regime for MYELOID HEMOPATHY
(CLO)-BALTIMORE	Fludarabine	BALTIMORE conditioning regime for LYMPHOID HEMOPATHY CLO-BALTIMORE conditioning regime for MYELOID HEMOPATHY
(CLO)-BALTIMORE	Cycophosphamide	BALTIMORE conditioning regime for LYMPHOID HEMOPATHY CLO-BALTIMORE conditioning regime for MYELOID HEMOPATHY
TBF	Donor Lymphocytes Injection	Conditioning regimen for LYMPHOID AND MYELOID HEMOPATHY
TBF	Post-Transplant Cyclophosphamide	Conditioning regimen for LYMPHOID AND MYELOID HEMOPATHY
(CLO)-BALTIMORE	Graft nuclear cells	BALTIMORE conditioning regime for LYMPHOID HEMOPATHY CLO-BALTIMORE conditioning regime for MYELOID HEMOPATHY
(CLO)-BALTIMORE	Donor Lymphocytes Injection	BALTIMORE conditioning regime for LYMPHOID HEMOPATHY CLO-BALTIMORE conditioning regime for MYELOID HEMOPATHY
(CLO)-BALTIMORE	total body irradiation	BALTIMORE conditioning regime for LYMPHOID HEMOPATHY CLO-BALTIMORE conditioning regime for MYELOID HEMOPATHY
TBF	hematopoietic stem cells	Conditioning regimen for LYMPHOID AND MYELOID HEMOPATHY
TBF	Thiotepa	Conditioning regimen for LYMPHOID AND MYELOID HEMOPATHY
TBF	Anti-Thymoglobulin	Conditioning regimen for LYMPHOID AND MYELOID HEMOPATHY
TBF	Busulfan	Conditioning regimen for LYMPHOID AND MYELOID HEMOPATHY
TBF	Graft nuclear cells	Conditioning regimen for LYMPHOID AND MYELOID HEMOPATHY
TBF	Methotrexate	Conditioning regimen for LYMPHOID AND MYELOID HEMOPATHY
(CLO)-BALTIMORE	Clofarabine	BALTIMORE conditioning regime for LYMPHOID HEMOPATHY CLO-BALTIMORE conditioning regime for MYELOID HEMOPATHY
TBF	Fludarabine	Conditioning regimen for LYMPHOID AND MYELOID HEMOPATHY

Primary Outcome Measures

Name	Time	Method
Incidence of grade 3-4 acute GVHD following allo-CSH for all patients and for each conditioning group (Baltimore and TBF).	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 Outcome Measures

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

Trial Locations

Locations (3)

CHU Angers; 🇫🇷 Angers, France

CHU Brest; 🇫🇷 Brest, France

CHU Nantes; 🇫🇷 Nantes, France