Overview
Sponsor-declared trial summary
Phase
Therapeutic exploratory (Phase II)
Status
Ongoing, recruiting
Participants planned
82
Countries
1
Sites
3
Adults patients will be included in the hematology departments. Eligible patients will be those scheduled to receive an allo-HSC after a RIC conditioning regimen for a myeloid or lymphoid hematological malignancy with a family or non-family HLA-matched donor 10/10
To estimate the incidence of grade 3-4 corticoresistant acute GVHD following allo-CSH (excluding post-DLI acute GVHD) for all patients and for each conditioning group (Baltimore and TBF)
Key facts
- Sponsor
- Centre Hospitalier Universitaire De Nantes
- Participant type
- Patients
- Age range
- 18-64 years, 65+ years
- Gender
- Male and Female
- Therapeutic area
- Diseases [C] - Immune System Diseases [C20], Diseases [C] - Hemic and Lymphatic Diseases [C15]
- Trial duration
- 18 Jul 2024 → ongoing
- Decision date (initial)
- 2024-04-08
- Transition trial
- No
- Low-intervention
- No
- Rare-disease indication
- No
- Vulnerable population
- No
- Funding sources
- DGOS PHRC inter-régional 2022
External identifiers
- EU CT number
- 2023-509042-35-01
- ClinicalTrials.gov
- NCT06252870
Trial design
CTIS Part I — objectives, methods, condition coding
Main objective
Scope: Safety
To estimate the incidence of grade 3-4 corticoresistant acute GVHD following allo-CSH (excluding post-DLI acute GVHD) for all patients and for each conditioning group (Baltimore and TBF)
Secondary objectives 12
- Incidence of engraftment (on the total population and for each conditioning group (Baltimore and TBF))
- Overall survival (OS) (on the total population and for each conditioning group (Baltimore and TBF))
- Disease-free survival (DFS) (on the total population and for each conditioning group (Baltimore and TBF))
- GVH-free and relapse-free survival (GRFS) (on the total population and for each conditioning group (Baltimore and TBF))
- Incidence of acute GVH grade 2-4 (on the total population and for each conditioning group (Baltimore and TBF))
- Incidence of chronic GVH (on the total population and for each conditioning group (Baltimore and TBF))
- Incidence of non-relapse mortality (NRM) (on the total population and for each conditioning group (Baltimore and TBF))
- Incidence of relapse (on the total population and for each conditioning group (Baltimore and TBF))
- Study of chimerism (on the total population and for each conditioning group (Baltimore and TBF))
- Immune reconstitution: T, NK, B lymphocytes and monocytes (on the total population and for each conditioning group (Baltimore and TBF))
- Grade 3 and 4 post-transplant adverse events (on the total population and for each conditioning group (Baltimore and TBF))
- Incidence of viral, bacteriological, fungal and parasitic infections (on the total population and for each conditioning group (Baltimore and TBF))
Conditions and MedDRA coding
Adults patients will be included in the hematology departments. Eligible patients will be those scheduled to receive an allo-HSC after a RIC conditioning regimen for a myeloid or lymphoid hematological malignancy with a family or non-family HLA-matched donor 10/10
Study design 2 periods
| # | Title | Allocation | Blinding | Roles blinded | Arms |
|---|---|---|---|---|---|
| 1 | overall trial Phase 2 muticentric randomized 1: 1 open prospective study aiming is to estimate the incidence of corticoresistant grade 3-4 acute GVHD following allo-CSH (excluding post-DLI acute GVHD) for all patients eligible to HSC allograft and for each conditioning regimen group (RIC conditioning regiemn Baltimore and TBF).
Randomization will be open-ended and unstratified. It will be carried out according to a 1:1 ratio and will be balanced by blocks of variable size. Randomization will be performed in Ennov Clinical by connecting to the website. The randomization arm will be assigned automatically during randomization.
Randomization is non-controlled
|
Not Applicable | None | Baltimore conditioning regimen: Baltimore-type conditioning with either fludarabine for lymphoid pathologies, or clofarabine for myeloid pathologie is composed of: - fludarabine or clofarabine: 30 mg/m² on D-6/D-5-/D-4/D-3/D-2 - CY (cyclophosphamide): 14.5 mg/kg on D-6/D-5 - Total body irradiation: 2 grays on D-1 (doses of chemotherapy will not exceed a body surface area of 2 m²) - anti-thymoglobulin: ATG 2.5 mg/kg on D-2 Theh, GVH prophylaxis is identical according to the type of conditioning randomized Baltimore or TBF: - MTX: 15 mg/m² at D+1 then 10 mg/m² at D+4/D+6/D+11 - Post transplant CY (PTCY): 50 mg/kg at D+3/D+5 MTX (experimental drug) is a solution for injection containing 5 g MTX in 50 mL. The excipient is sodium chloride 0.9%. MTX is administered by the venous route as a short infusion over 30 minutes. The drug is pre-diluted in 20ml of 0.9% sodium chloride solution. The administration of folinic acid 15 mg/m² is recommended within 6 to 24 hours after MTX injection. In the event of extravasation, administration should be stopped immediately. No dose adjustment is authorized. PTCY (auxiliary drug) is a powder for injectable solution : Cyclophosphamide anhydrous 1000.00 mg as cyclophosphamide 1069.00 mg for one vial. Excipient is sodium chloride. To prepare a ready-to-use isotonic solution, the powder should be dissolved in a 0.9% sodium chloride solution to bring the concentration to 1g per 50ml. If required, it can also be dissolved in Ringer's solution, water for injection or glucose solution. The reconstituted solution should not be stored for longer than 48 hours, and should not exceed a concentration of 2%. The usual route of administration is venous infusion over 1 hour. The drug, reconstituted in 0.9% sodium chloride solution, is introduced into the infusion fluid (isotonic glucose or sodium chloride solution for injection). It is recommended to combine the administration of Uromitexan from 600 mg/m²/d and/or to ensure adequate hydration. In the event of extravasation, administration should be stopped immediately. No dose adjustment is authorized, as it is not intended to include patients with renal impairment (creatinine clearance < 60 ml/min). |
|
| 2 | overall trial Phase 2 muticentric randomized 1: 1 open prospective study aiming is to estimate the incidence of corticoresistant grade 3-4 acute GVHD following allo-CSH (excluding post-DLI acute GVHD) for all patients eligible to HSC allograft and for each conditioning regimen group (RIC conditioning regiemn Baltimore and TBF).
Randomization will be open-ended and unstratified. It will be carried out according to a 1:1 ratio and will be balanced by blocks of variable size. Randomization will be performed in Ennov Clinical by connecting to the website. The randomization arm will be assigned automatically during randomization.
Randomization is non-controlled
|
Not Applicable | None | TBF conditioning regimen: TBF conditioning for patients with myeloid and lymphoid hemopathies is unique and composed of: - thiotepa: 5 mg/kg at D-6 - busulfan: 3.2mg/kg at D-2 and D-1 - fludarabine: 40 mg/m² at D-5/D-4/D-3/D-2 - ATG: 2.5 mg/kg on D-1 Theh, GVH prophylaxis is identical according to the type of conditioning randomized Baltimore or TBF: - MTX: 15 mg/m² at D+1 then 10 mg/m² at D+4/D+6/D+11 - Post transplant CY (PTCY): 50 mg/kg at D+3/D+5 MTX (experimental drug) is a solution for injection containing 5 g MTX in 50 mL. The excipient is sodium chloride 0.9%. MTX is administered by the venous route as a short infusion over 30 minutes. The drug is pre-diluted in 20ml of 0.9% sodium chloride solution. The administration of folinic acid 15 mg/m² is recommended within 6 to 24 hours after MTX injection. In the event of extravasation, administration should be stopped immediately. No dose adjustment is authorized. PTCY (auxiliary drug) is a powder for injectable solution : Cyclophosphamide anhydrous 1000.00 mg as cyclophosphamide 1069.00 mg for one vial. Excipient is sodium chloride. To prepare a ready-to-use isotonic solution, the powder should be dissolved in a 0.9% sodium chloride solution to bring the concentration to 1g per 50ml. If required, it can also be dissolved in Ringer's solution, water for injection or glucose solution. The reconstituted solution should not be stored for longer than 48 hours, and should not exceed a concentration of 2%. The usual route of administration is venous infusion over 1 hour. The drug, reconstituted in 0.9% sodium chloride solution, is introduced into the infusion fluid (isotonic glucose or sodium chloride solution for injection). It is recommended to combine the administration of Uromitexan from 600 mg/m²/d and/or to ensure adequate hydration. In the event of extravasation, administration should be stopped immediately. No dose adjustment is authorized, as it is not intended to include patients with renal impairment (creatinine clearance < 60 ml/min). |
Regulatory references
- Plan to share IPD
- No
| EU CT number | Title | Sponsor |
|---|---|---|
| 2023-509042-35-00 | 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 _ CY-MET-RIC | Centre Hospitalier Universitaire De Nantes |
Eligibility criteria
Principal inclusion / exclusion criteria as submitted by sponsor
Inclusion criteria 11
- Age: ≥ 18 and ≤ 70 years
- Patient with hematologic malignancy
- Indication for allogeneic haematopoietic stem cell transplantation with attenuated conditioning
- Peripheric stem cell graft
- Availability of an HLA-matched 10/10 family or non-family donor
- Protocol consent
- ECOG <=2
- Women of childbearing age with negative pregnancy test and on highly effective contraception during treatment and for 12 months after discontinuation of CY and MTX
- Men of childbearing age with effective contraception during treatment and for 6 months after stopping CY and MTX
- Hepatitis B, C and HIV serologies negative.
- Social security affiliation
Exclusion criteria 17
- Prior allograft transplantation
- Patient eligible for myeloablative conditioning (MAC)
- Bone marrow graft
- Other active cancer disease, or history of cancer in the last two years, with the exception of skin carcinoma or carcinoma in situ of the uterine cervix treated and in remission
- Active psychiatric condition
- Pregnant or breast-feeding woman
- Women or men of childbearing age without effective contraception
- Severe, uncontrolled concomitant infection
- Cardiac: systolic ejection fraction < 50% by transthoracic echocardiography or isotopic method (isotopic gamma-angiography), NYHA II, III or IV heart failure, active rhythmic, valvular or ischemic heart disease or history of heart disease
- Respiratory: DLCOc < 40% of theoretical value on EFR
- Renal: creatinine clearance < 50 ml/min (assessed by MDRD method)
- Urological: active urinary tract infection, history of acute urothelial toxicity due to cytotoxic chemotherapy or radiotherapy, known obstruction of urinary outflow, pre-existing hemorrhagic cystitis
- Hepatic: transaminases greater than 5 times normal or bilirubin greater than 2 times normal
- Person protected by law (adult under guardianship, curatorship or safeguard of justice)
- accination against yellow fever within the last year
- Known or suspected hypersensitivity to rabbit proteins
- Patient does not speak French
Endpoints
Primary and secondary outcome measures (English text)
Primary endpoints 1
- The incidence of corticoresistant grade 3 and 4 acute GVH following allo-HSC according to Mount Sinai criteria. Corticoresistance is assessed according to the criteria of Mohty et al and defined as either -> after 5 to 7 days of 2 mg/kg systemic corticosteroids: worsening or non-improvement of GVH -> after 14 days of 2 mg/kg systemic corticosteroids: absence of complete remission of GVHD. Corticoresistant acute GVH following DLI injection will be excluded
Secondary endpoints 12
- Graft uptake assessed on hematological reconstitution (number of days of aplasia with PNN <0.5 G/L and platelets < 20, number of platelet and red cell concentrate transfusions)
- OS at 1 year and last follow-up (survival between day 0 of transplantation and date of death or last follow-up)
- DFS at 1 year and last follow-up (survival from day 0 of transplantation to date of relapse, death or last follow-up)
- GRFS at 1 year and last follow-up (relapse-free survival without grade 3-4 acute GVH or chronic GVH requiring systemic treatment)
- Acute GVHD grade 2-4 according to Mount Sinai criteria
- Chronic GVHD according to NCI criteria
- NRM: any death unrelated to relapse or disease progression at 1 year and last follow-up
- Relapse: any documented disease recurrence at 1 year and last follow-up
- Total donor or mixed chemism at M1, M2, M3, M6, M12. Total donor chimerism = result >95% donor CD3+ and CD34+ cells. Mixed chimerism = result > 5% and < 95% donor CD3+ cells (routine test)
- Immune reconstitution at M3, M6, M9, M12: lymphocyte, monocyte, T4, T8, NK and B cell counts (routine examination)
- Grade 3 and 4 post-transplant adverse events (dates of occurrence) (NCI CTCAE version 5 criteria)
- Infections: viral (CMV, EBV, BKV, adenovirus), bacteriological, fungal and parasitic
Investigational products
Investigational medicinal products (IMPs), comparators, placebo, auxiliary
Test 2
SUB06859MIG · Substance
- Active substance
- Cyclophosphamide
- Pharmaceutical form
- SOLUTION FOR INJECTION/INFUSION
- Route of administration
- INTRAVENOUS USE
- Max daily dose
- 50 mg/kg milligram(s)/kilogram
- Max total dose
- 100 mg/kg milligram(s)/kilogram
- Max treatment duration
- 2 Day(s)
- Authorisation status
- Authorised
- ATC code
- - — -
- Marketing authorisation
- -
- Paediatric formulation
- No
- Orphan designation
- No
- Modified vs. Marketing Authorisation
- No
SUB08856MIG · Substance
- Active substance
- Methotrexate
- Pharmaceutical form
- SOLUTION FOR INJECTION
- Route of administration
- INTRAVENOUS USE
- Max daily dose
- 15 mg/m2 milligram(s)/sq. meter
- Max total dose
- 60 mg/m2 milligram(s)/sq. meter
- Max treatment duration
- 11 Day(s)
- Authorisation status
- Authorised
- ATC code
- - — -
- Marketing authorisation
- -
- Paediatric formulation
- No
- Orphan designation
- No
- Modified vs. Marketing Authorisation
- Yes
- Modification description
- Labelling
Auxiliary 6
SUB05993MIG · Substance
- Active substance
- Busulfan
- Pharmaceutical form
- CONCENTRATE FOR SOLUTION FOR INJECTION
- Route of administration
- INTRAVENOUS USE
- Max daily dose
- 3.2 mg/kg milligram(s)/kilogram
- Max total dose
- 6.4 mg/kg milligram(s)/kilogram
- Max treatment duration
- 2 Day(s)
- Authorisation status
- Authorised
- ATC code
- - — -
- Marketing authorisation
- -
- Paediatric formulation
- No
- Orphan designation
- No
- Modified vs. Marketing Authorisation
- No
SUB06859MIG · Substance
- Active substance
- Cyclophosphamide
- Pharmaceutical form
- INJECTION/INFUSION
- Route of administration
- INTRAVENOUS USE
- Max daily dose
- 14.5 mg/kg milligram(s)/kilogram
- Max total dose
- 29 mg/kg milligram(s)/kilogram
- Max treatment duration
- 2 Day(s)
- Authorisation status
- Authorised
- ATC code
- - — -
- Marketing authorisation
- -
- Paediatric formulation
- No
- Orphan designation
- No
- Modified vs. Marketing Authorisation
- No
Anti-Human T-Lymphocyte Immunoglobulin From Rabbits
SUB21246 · Substance
- Active substance
- Anti-Human T-Lymphocyte Immunoglobulin From Rabbits
- Pharmaceutical form
- SOLUTION FOR INFUSION
- Route of administration
- INTRAVENOUS USE
- Max daily dose
- 2.5 mg/kg milligram(s)/kilogram
- Max total dose
- 2.5 mg/kg milligram(s)/kilogram
- Max treatment duration
- 1 Day(s)
- Authorisation status
- Authorised
- ATC code
- - — -
- Marketing authorisation
- -
- Paediatric formulation
- No
- Orphan designation
- No
- Modified vs. Marketing Authorisation
- No
SUB10985MIG · Substance
- Active substance
- Thiotepa
- Pharmaceutical form
- SOLUTION FOR INJECTION/INFUSION
- Route of administration
- INTRAVENOUS USE
- Max daily dose
- 5 mg/kg milligram(s)/kilogram
- Max total dose
- 5 mg/kg milligram(s)/kilogram
- Max treatment duration
- 1 Day(s)
- Authorisation status
- Authorised
- ATC code
- - — -
- Marketing authorisation
- -
- Paediatric formulation
- No
- Orphan designation
- No
- Modified vs. Marketing Authorisation
- No
SUB07678MIG · Substance
- Active substance
- Fludarabine
- Pharmaceutical form
- SOLUTION FOR INJECTION/INFUSION
- Route of administration
- INTRAVENOUS USE
- Max daily dose
- 30 mg/m2 milligram(s)/sq. meter
- Max total dose
- 150 mg/m2 milligram(s)/sq. meter
- Max treatment duration
- 5 Day(s)
- Authorisation status
- Authorised
- ATC code
- - — -
- Marketing authorisation
- -
- Paediatric formulation
- No
- Orphan designation
- No
- Modified vs. Marketing Authorisation
- No
SUB21902 · Substance
- Active substance
- Clofarabine
- Pharmaceutical form
- SOLUTION FOR INFUSION
- Route of administration
- INTRAVENOUS USE
- Max daily dose
- 30 mg/m2 milligram(s)/sq. meter
- Max total dose
- 150 mg/m2 milligram(s)/sq. meter
- Max treatment duration
- 5 Day(s)
- Authorisation status
- Authorised
- ATC code
- - — -
- Marketing authorisation
- -
- Paediatric formulation
- No
- Orphan designation
- No
- Modified vs. Marketing Authorisation
- No
Sponsors and contacts
Sponsor organisations, regulatory contacts, third parties
Centre Hospitalier Universitaire De Nantes
- Sponsor organisation
- Centre Hospitalier Universitaire De Nantes
- Address
- 5 Allee De L Ile Gloriette, Cs 69301 Cs 69301
- City
- Nantes Cedex 1
- Postcode
- 44093
- Country
- France
Scientific contact point
- Organisation
- Centre Hospitalier Universitaire De Nantes
- Contact name
- Dr Amandine Le Bourgeois
Public contact point
- Organisation
- Centre Hospitalier Universitaire De Nantes
- Contact name
- Dr Amandine Le Bourgeois
Locations
1 EU/EEA country · 3 investigational sites
By country
| Country | MS status | Planned subjects | Sites |
|---|---|---|---|
| France | Ongoing, recruiting | 82 | 3 |
| Rest of world | — | 0 | — |
Investigational sites
Centre Hospitalier Universitaire De Nantes
Hematology, 1 Place Alexis Ricordeau, 44000, Nantes
Centre Hospitalier Universitaire D'Angers
Hematology, 4 Rue Larrey, 49100, Angers
Centre Hospitalier Regional Et Universitaire De Brest
Hematology, 5 Avenue Marechal Foch, Bp 824, Brest Cedex 2
Country notifications
Trial-start, recruitment-start, end and early-termination notifications submitted per Member State
| Country | Trial start | Trial end | Recruitment start | Recruitment end | Early termination |
|---|---|---|---|---|---|
| France | 2024-07-18 | 2024-07-18 |
Results and documents
Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial
Documents 5 files
Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.
| Type | Title | Version |
|---|---|---|
| Protocol (for publication) | D1_Protocol 2023-509042-35-00 Redacted | 4.0 |
| Recruitment arrangements (for publication) | K1_recruitment arrangements | 1 |
| Subject information and informed consent form (for publication) | L1_ SIS and ICF adult | 2.0 |
| Summary of Product Characteristics (SmPC) (for publication) | G2_SmPC_Methotrexate_2023-04-04 | 1 |
| Synopsis of the protocol (for publication) | D1_Protocol synopsis MS FR 2023-509042-35-00 | 2.0 |
Application history
4 submissions — initial application plus substantial / non-substantial modifications
| # | Type | Code | Submitted | Reference MS | Conclusion | Decision date |
|---|---|---|---|---|---|---|
| 1 | INITIAL | IN | 2024-01-15 | France | Acceptable 2024-04-05
|
2024-04-08 |
| 2 | SUBSTANTIAL MODIFICATION | SM-1 | 2024-06-11 | France | Acceptable 2024-08-23
|
2024-08-23 |
| 3 | SUBSTANTIAL MODIFICATION | SM-2 | 2025-02-03 | France | Acceptable 2025-03-20
|
2025-03-20 |
| 4 | SUBSTANTIAL MODIFICATION | SM-3 | 2025-05-22 | France | Acceptable 2025-06-19
|
2025-06-19 |