Study Comparing the Efficacy of 2 RIC Regimens (Clofarabine vs Fludarabine) in Adults With AML Eligible to Allo-SCT

Official title

FLUCLORIC: Randomized Multicentric Phase III Study Comparing the Efficacy of 2 Reduced Intensity Conditioning Regimens (Clofarabine/Busulfan vs Fludarabine/Busulfan) in Adults With AML and Eligible to Allogeneic Stem Cell Transplantation

Overview

Relapse remains the main cause of death in patients with myeloid malignancies, especially after an allotransplant. Using drugs with higher anti-leukemic activity as part of the conditioning regimen is one of the strategies to decrease relapse incidence in this population. Retrospective studies have shown that clofarabine can achieve impressive results compared to the use of fludarabine in acute myeloid leukemia (AML) as part of the conditioning regimen. Confirming such results in a prospective manner would definitely establish the CloB2A2 as a superior reduced-intensity conditioning (RIC) regimen compared to the FB2A2 for AML patients.302 AML patients (151 in each arm) in complete remission at transplant will be included with the main objective to demonstrate a significant better 2-year overall survival for CloB2A2 cases (70% vs 55%). A cost-utility analysis and a cost-effectiveness analysis will be also performed as well as an assessment of the quality of life after transplant. Clofarabine will be furnished to all centers. The duration of the study will be 5 years with 3 years of inclusion and 2 years of follow-up for each patient.

Interventions

• Drug Fludarabine
  30 mg/m2/day IV fludarabine for 5 days (day-6 to day-2)
• Drug Busulfan
  130 mg/m2/day IV busulfan once daily for 2 days (day -4 and -3)
• Drug ATG
  Thymoglobuline®: 2.5 mg/Kg/day IV for 2 consecutive days (day -2 and -1)
• Drug Clofarabine
  30 mg/m2/day IV clofarabine for 5 days (day-6 to day-2)

Primary outcome measures

• To compare 2-year OS between patients with AML in complete remission receiving either a CloB2A2 or a FB2A2 RIC regimen for allo-SCT. [Time frame: 2 years]

Secondary outcome measures (12)

• To compare between AML patients in complete remission receiving either a CloB2A2 or a FB2A2 RIC regimen for allo-SCT: Engraftment, primary and secondary graft failure [Time frame: day +30/42 and 2 years]
• To compare between AML patients in complete remission receiving either a CloB2A2 or a FB2A2 RIC regimen for allo-SCT: Neutrophils and platelet recoveries [Time frame: 2 years]
• To compare between AML patients in complete remission receiving either a CloB2A2 or a FB2A2 RIC regimen for allo-SCT: 2-year DFS [Time frame: 2 years]
• To compare between AML patients in complete remission receiving either a CloB2A2 or a FB2A2 RIC regimen for allo-SCT:-2-year relapse incidence [Time frame: 2 years]
• To compare between AML patients in complete remission receiving either a CloB2A2 or a FB2A2 RIC regimen for allo-SCT:2-year NRM [Time frame: 2 years]
• To compare between AML patients in complete remission receiving either a CloB2A2 or a FB2A2 RIC regimen for allo-SCT:Incidence of acute and chronic graft versus host disease (GVHD) [Time frame: Day 90 and 2 years]
• To compare between AML patients in complete remission receiving either a CloB2A2 or a FB2A2 RIC regimen for allo-SCT:Incidence of GVHD free relapse free survival (GRFS) [Time frame: 2 years]
• To compare between AML patients in complete remission receiving either a CloB2A2 or a FB2A2 RIC regimen for allo SCT:Chimerism [Time frame: days +30, +60, +90]
• To compare between AML patients in complete remission receiving either a CloB2A2 or a FB2A2 RIC regimen for allo- SCT:Immune reconstitution [Time frame: 3, 6 and 12 months]
• To compare between AML patients in complete remission receiving either a CloB2A2 or a FB2A2 RIC regimen for allo- SCT: Minimal residual disease (MRD) [Time frame: days +30 and +90]
• Comparison of infections after FB2A2 vs CloB2A2: bacterial, viral, parasitic and fungal [Time frame: day+90]
• Quality of life using the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) [Time frame: Days -7, +30, +90, +180, +360 and +720]

Eligibility criteria

Inclusion criteria

Age ≥ 18 years' old

• De novo or secondary AML (according to ELN 2022 classification) in complete cytological remission at time of transplant (bone marrow blast count < 5%) or MDS/LAM with bone marrow blast count ≤ 5%
• Patients in first or second line therapy are allowed
• Patient eligible to a RIC regimen : patients aged ≥ 60 year old or <60 with co-morbidity(ies).
• Patient with a related or an unrelated matched donor
• Graft using only peripheral blood stem cells
• Performance status ECOG 0 - 2
• Who provide their written informed consent
• Previous allograft allowed
• Affiliated with French social security system or beneficiary from such system
• Women must meet one of the following criteria at the time of inclusion:

• use adequate contraceptive measures as recommended by the CTFG (Recommendations related to contraception and pregnancy testing in clinical trials v1.1; includes injectable implants, dual hormone birth control pills, intrauterine devices, abstinence from sex, or a sterilized partner), and have a negative pregnancy test (urine or serum pregnancy test) prior to receiving the first dose of study drug;
• or be post-menopausal (over 50 years of age with amenorrhea for at least 12 months after discontinuation of all exogenous hormonal therapy)
• or (if under 50 years of age) have been amenorrheic for at least 12 months after discontinuation of exogenous hormonal therapy and with luteinizing hormone (LH) and follicle stimulating hormone (FSH) levels corresponding to post-menopausal levels
• or have undergone irreversible surgical sterilization by hysterectomy, bilateral oophorectomy or bilateral salpingectomy (this operation must be documented).
• Contraception methods must be prescribed using effective contraceptive methods during treatment and within 6 months for women of childbearing age (WOCB) and 6 months for men in case they have sexual relations with WOCB after the last dose of Fludarabine/Clofarabine.

Exclusion criteria

• Pro-myelocytic leukemia
• Patient eligible to a myeloablative conditioning regimen
• Patient with haploidentical, mismatched unrelated donor or umbilical cord blood
• Pregnant or breastfeeding woman or patient refusing contraceptive mesures
• HIV positive
• Active Hepatitis B or C
• Left ventricular ejection fraction < 50%.
• DLCOc <40%
• Uncontrolled infection
• Uncontrolled haemolytic anaemia
• Creatinine clearance < 50 ml/min (evaluated by MDRD or CKDEPI).
• Serum bilirubine > 30 mmol/l, Cytolysis > 5 the upper limit range
• Previous or concurrent second malignancy except for adequately treated basal cell carcinoma of the skin, curatively treated in situ carcinoma of the cervix, curatively treated solid cancer, with no evidence of disease for at least 2 years
• Any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule
• Participation to another interventional study during the last month or expected participation to another interventional study during participation to the FLUCLORIC study.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

France · 23 centers

• CHU de Nantes — Nantes
• CHU Amiens — Amiens
• CHU Angers — Angers
• CHU Besançon — Besançon
• CHU Bordeaux — Bordeaux
• CHU Brest — Brest
• CRLC Caen — Caen
• CHU Clermont-Ferrand — Clermont-Ferrand
• … and 15 more centers

Identifiers

NCT: NCT05917405 · RC22_0524

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗