Clinical trial • Phase II • Immunology|Haematology

METHOTREXATE for Myeloid hematological malignancy | Lymphoid hematological malignancy

Phase II trial of METHOTREXATE for Myeloid hematological malignancy | Lymphoid hematological malignancy.

Overview

Trial Therapeutic Area: Immunology|Haematology
Trial Disease: Myeloid hematological malignancy | Lymphoid hematological malignancy
Trial Stage: Phase II
Drug Modality: Small molecule|Other antibody

Key dates

Initial CTIS Submission Date: 15-01-2024
First CTIS Authorization Date: 08-04-2024

Trial design

Randomised, open-label, two conditioning regimen arms compared: (1) baltimore-type conditioning: fludarabine or clofarabine 30 mg/m² on d-6/d-5/d-4/d-3/d-2 (fludarabine used for lymphoid pathologies, clofarabine for myeloid), cyclophosphamide 14.5 mg/kg on d-6/d-5, total body irradiation 2 grays on d-1, atg 2.5 mg/kg on d-2; gvhd prophylaxis: mtx 15 mg/m² d+1 then 10 mg/m² d+4/d+6/d+11 and post-transplant cyclophosphamide (ptcy) 50 mg/kg at d+3 and d+5. (2) tbf conditioning: thiotepa 5 mg/kg at d-6, busulfan 3.2 mg/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; same gvhd prophylaxis as above (mtx and ptcy).-controlled Phase II trial in France.

Randomised: Yes
Open Label: Yes
Comparator: Two conditioning regimen arms compared: (1) Baltimore-type conditioning: fludarabine or clofarabine 30 mg/m² on D-6/D-5/D-4/D-3/D-2 (fludarabine used for lymphoid pathologies, clofarabine for myeloid), cyclophosphamide 14.5 mg/kg on D-6/D-5, total body irradiation 2 grays on D-1, ATG 2.5 mg/kg on D-2; GVHD prophylaxis: MTX 15 mg/m² D+1 then 10 mg/m² D+4/D+6/D+11 and post-transplant cyclophosphamide (PTCY) 50 mg/kg at D+3 and D+5. (2) TBF conditioning: thiotepa 5 mg/kg at D-6, busulfan 3.2 mg/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; same GVHD prophylaxis as above (MTX and PTCY).
Target Sample Size: 82
Trial Duration For Participant: 365

Eligibility

Recruits 82 Persons protected by law (adults under guardianship, curatorship or safeguard of justice) are explicitly excluded. Only adults (Age ≥ 18 and ≤ 70 years) able to provide protocol consent are eligible; a subject information sheet and adult informed consent form are provided. Patients must speak French (exclusion: 'Patient does not speak French'). No paediatric consent/assent procedures are applicable..

Pregnancy Exclusion: Pregnant or breast-feeding woman
Vulnerable Population: Persons protected by law (adults under guardianship, curatorship or safeguard of justice) are explicitly excluded. Only adults (Age ≥ 18 and ≤ 70 years) able to provide protocol consent are eligible; a subject information sheet and adult informed consent form are provided. Patients must speak French (exclusion: 'Patient does not speak French'). No paediatric consent/assent procedures are applicable.

Inclusion criteria

{"criterion_text":"- Age: ≥ 18 and ≤ 70 years\n- Hepatitis B, C and HIV serologies negative.\n- Social security affiliation\n- Patient with hematologic malignancy\n- Indication for allogeneic haematopoietic stem cell transplantation with attenuated conditioning\n- Peripheric stem cell graft\n- Availability of an HLA-matched 10/10 family or non-family donor\n- Protocol consent\n- ECOG <=2\n- 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\n- Men of childbearing age with effective contraception during treatment and for 6 months after stopping CY and MTX"}

Exclusion criteria

{"criterion_text":"- Prior allograft transplantation\n- Respiratory: DLCOc < 40% of theoretical value on EFR\n- Renal: creatinine clearance < 50 ml/min (assessed by MDRD method)\n- 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\n- Hepatic: transaminases greater than 5 times normal or bilirubin greater than 2 times normal\n- Person protected by law (adult under guardianship, curatorship or safeguard of justice)\n- accination against yellow fever within the last year\n- Known or suspected hypersensitivity to rabbit proteins\n- Patient does not speak French\n- Patient eligible for myeloablative conditioning (MAC)\n- Bone marrow graft\n- 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\n- Active psychiatric condition\n- Pregnant or breast-feeding woman\n- Women or men of childbearing age without effective contraception\n- Severe, uncontrolled concomitant infection\n- 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"}

Endpoints

Primary endpoints

{"endpoint_text":"- 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","definition_or_measurement_approach":"Assessed according to Mount Sinai criteria; corticoresistance per Mohty et al defined as (1) after 5–7 days of 2 mg/kg systemic corticosteroids: worsening or non-improvement of GVH, or (2) after 14 days of 2 mg/kg systemic corticosteroids: absence of complete remission. Acute GVH following DLI injection excluded."}

Secondary endpoints

{"endpoint_text":"- 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)\n- OS at 1 year and last follow-up (survival between day 0 of transplantation and date of death or last follow-up)\n- DFS at 1 year and last follow-up (survival from day 0 of transplantation to date of relapse, death or last follow-up)\n- GRFS at 1 year and last follow-up (relapse-free survival without grade 3-4 acute GVH or chronic GVH requiring systemic treatment)\n- Acute GVHD grade 2-4 according to Mount Sinai criteria\n- Chronic GVHD according to NCI criteria\n- NRM: any death unrelated to relapse or disease progression at 1 year and last follow-up\n- Relapse: any documented disease recurrence at 1 year and last follow-up\n- 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)\n- Immune reconstitution at M3, M6, M9, M12: lymphocyte, monocyte, T4, T8, NK and B cell counts (routine examination)\n- Grade 3 and 4 post-transplant adverse events (dates of occurrence) (NCI CTCAE version 5 criteria)\n- Infections: viral (CMV, EBV, BKV, adenovirus), bacteriological, fungal and parasitic","definition_or_measurement_approach":"Provided in protocol: graft uptake via hematological reconstitution metrics (days of aplasia with PNN <0.5 G/L and platelets <20, transfusion counts); OS/DFS/GRFS defined as survival/time-to-event between day 0 and event or last follow-up; chimerism thresholds given (>95% for total donor; >5% and <95% for mixed); immune cell counts at specified months (routine tests); grade 3-4 AEs per NCI CTCAE v5; infections specified including listed viral agents."}

Recruitment

Planned Sample Size: 82
Recruitment Window Months: 48
Consent Approach: Informed consent is required ('Protocol consent' inclusion criterion). A subject information sheet and adult informed consent form (L1 SIS and ICF adult) are provided. Only adults (≥18 years) who can give consent and who speak French are eligible; no paediatric assent procedures are described.

Geography

Total Number Of Sites: 3
Total Number Of Participants: 82

France

Earliest CTIS Part Ii Submission Date: 19-01-2024
Latest Decision Or Authorization Date: 19-06-2025
Processing Time Days: 517
Number Of Sites: 3
Number Of Participants: 82

Sites

Site Name: Centre Hospitalier Universitaire D'Angers
Department Name: Hematology
Contact Person Name: Sylvain THEPOT
Contact Person Email: Sylvain.Thepot@chu-angers.fr

Site Name: Centre Hospitalier Universitaire De Nantes
Department Name: Hematology
Contact Person Name: Amandine LE BOURGEOIS
Contact Person Email: amandine.lebourgeois@chu-nantes.fr

Site Name: Centre Hospitalier Regional Et Universitaire De Brest
Department Name: Hematology
Contact Person Name: Marie-Anne COUTURIER
Contact Person Email: marie-anne.couturier@chu-brest.fr

Sponsor

Primary sponsor

Full Name: Centre Hospitalier Universitaire De Nantes
Organisation Type: Hospital/Clinic/Other health care facility
Country Of Registered Address: France

Investigational products

Investigational Product Name: METHOTREXATE
Active Substance: METHOTREXATE
Modality: Small molecule
Routes Of Administration: INTRAVENOUS USE
Route: Intravenous
Starting Dose: 15 mg/m² at D+1 (MTX prophylaxis); then 10 mg/m² at D+4/D+6/D+11
Dose Levels: 15 mg/m² then 10 mg/m² doses as per schedule
Frequency: Single-dose at specified post-transplant days (D+1, D+4, D+6, D+11)
Maximum Dose: maxDailyDoseAmount 15 mg/m2 (product record); maxTotalDoseAmount 60 mg/m2

Investigational Product Name: CYCLOPHOSPHAMIDE
Active Substance: CYCLOPHOSPHAMIDE
Modality: Small molecule
Routes Of Administration: INTRAVENOUS USE
Route: Intravenous
Starting Dose: 14.5 mg/kg on D-6 and D-5 (conditioning, Baltimore); post-transplant cyclophosphamide (PTCY) 50 mg/kg at D+3 and D+5 (GVHD prophylaxis)
Dose Levels: conditioning dose 14.5 mg/kg (Baltimore) and PTCY 50 mg/kg (post-transplant)
Frequency: Conditioning doses on specified pre-transplant days; PTCY on D+3 and D+5
Maximum Dose: product records show maxDailyDoseAmount entries (e.g. 50 mg/kg in one record)

Investigational Product Name: BUSULFAN
Active Substance: BUSULFAN
Modality: Small molecule
Routes Of Administration: INTRAVENOUS USE
Route: Intravenous
Starting Dose: 3.2 mg/kg at D-2 and D-1 (TBF regimen)
Dose Levels: 3.2 mg/kg administered on two days
Frequency: D-2 and D-1
Maximum Dose: maxDailyDoseAmount 3.2 mg/kg; maxTotalDoseAmount 6.4 mg/kg

Investigational Product Name: ANTI-HUMAN T-LYMPHOCYTE IMMUNOGLOBULIN FROM RABBITS
Active Substance: ANTI-HUMAN T-LYMPHOCYTE IMMUNOGLOBULIN FROM RABBITS
Modality: Other antibody
Routes Of Administration: INTRAVENOUS USE
Route: Intravenous
Starting Dose: ATG 2.5 mg/kg (timing varies by regimen: D-2 in Baltimore; D-1 in TBF)
Dose Levels: Single dosing as per regimen 2.5 mg/kg
Frequency: Single administration on specified pre-transplant day
Maximum Dose: maxDailyDoseAmount 2.5 mg/kg

Investigational Product Name: THIOTEPA
Active Substance: THIOTEPA
Modality: Small molecule
Routes Of Administration: INTRAVENOUS USE
Route: Intravenous
Starting Dose: 5 mg/kg at D-6 (TBF regimen)
Dose Levels: Single dose of 5 mg/kg
Frequency: Single administration on D-6
Maximum Dose: maxDailyDoseAmount 5 mg/kg

Investigational Product Name: FLUDARABINE
Active Substance: FLUDARABINE
Modality: Small molecule
Routes Of Administration: INTRAVENOUS USE
Route: Intravenous
Starting Dose: 30 mg/m² on D-6/D-5/D-4/D-3/D-2 (Baltimore for lymphoid) or 40 mg/m² at D-5/D-4/D-3/D-2 (TBF regimen as described)
Dose Levels: 30–40 mg/m² depending on regimen
Frequency: Daily over specified pre-transplant days
Maximum Dose: product records show maxDailyDoseAmount 30 mg/m2 in one record and 40 mg/m2 described in regimen text

Investigational Product Name: CLOFARABINE
Active Substance: CLOFARABINE
Modality: Small molecule
Routes Of Administration: INTRAVENOUS USE
Route: Intravenous
Starting Dose: 30 mg/m² on D-6/D-5/D-4/D-3/D-2 (used in Baltimore for myeloid pathologies)
Dose Levels: 30 mg/m² per day on specified days
Frequency: Daily over specified pre-transplant days
Maximum Dose: maxDailyDoseAmount 30 mg/m2; maxTotalDoseAmount 150 mg/m2

Combination Treatment: Yes

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