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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Acute Myeloid Leukemia in Remission

Intervention / Treatment
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* Drug: Fludarabine
* Drug: Busulfan
* Drug: ATG
* Drug: Clofarabine


Participation Criteria
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Eligibility Criteria
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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%) 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%. DLCO <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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 99 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Experimental: CloB2 arm<br>30 mg/m2/day IV clofarabine for 5 days (day-6 to day-2) 130 mg/m2/day IV busulfan once daily for 2 days (day -4 and -3) ATG (Thymoglobuline®) 2.5 mg/Kg/day IV for 2 consecutive days (day -2 and -1) Corticosteroids may be used in profilaxis | Drug: Busulfan<br>* 130 mg/m2/day IV busulfan once daily for 2 days (day -4 and -3)<br>Drug: ATG<br>* Thymoglobuline®: 2.5 mg/Kg/day IV for 2 consecutive days (day -2 and -1)<br>Drug: Clofarabine<br>* 30 mg/m2/day IV clofarabine for 5 days (day-6 to day-2)<br>|
| Active Comparator: Comparator: FB2A2 arm<br>30 mg/m2/day IV fludarabine for 5 days (day-6 to day-2) 130 mg/m2/day IV busulfan once daily for 2 days (day -4 and -3) ATG (Thymoglobuline®) 2.5 mg/Kg/day IV for 2 consecutive days (day -2 and -1) | Drug: Fludarabine<br>* 30 mg/m2/day IV fludarabine for 5 days (day-6 to day-2)<br>Drug: Busulfan<br>* 130 mg/m2/day IV busulfan once daily for 2 days (day -4 and -3)<br>Drug: ATG<br>* Thymoglobuline®: 2.5 mg/Kg/day IV for 2 consecutive days (day -2 and -1)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To compare 2-year OS between patients with AML in complete remission receiving either a CloB2A2 or a FB2A2 RIC regimen for allo-SCT. | OS is defined as the time from day 1 of conditioning to death or last follow-up for survivors. | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | Engraftment: PNN >500/mm3 + donor chimerism >=5% (day +30/42) Primary and secondary graft failure: donor chimerism <5% at day +30/42 post-transplant (primary) or at distance of transplant after achieving engraftment (secondary) | 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 | Neutrophils recovery: the first of three consecutive days with neutrophils ≥500/mm3 after aplasia from day 0 of the graft Platelets recovery: the first of three consecutive days with platelets ≥20000/mm3 without transfusion after aplasia from day 0 of the graft | 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 | DFS: time from day1 of the conditioning to time without death or evidence of relapse or disease progression censored at the date of last follow-up. | 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 | Relapse: any event related to progression or re-occurrence of the disease from day 1 of the conditioning. | 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 | NRM: death from any cause without previous relapse or progression from day 1 of the conditioning | 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) | Acute GVHD: NIH criteria Chronic GVHD: NIH criteria | 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) | GRFS: alive with no previous grade III-IV acute GvHD, no moderate or severe chronic GvHD and no relapse from day 1 of the conditioning | 2 years | 
| To compare between AML patients in complete remission receiving either a CloB2A2 or a FB2A2 RIC regimen for allo SCT:Chimerism | Chimerism: peripheral blood and CD3 T cells by molecular markers at days +30, +60, +90/100 | 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 | Immune reconstitution: Immunophenotype of PB lymphocytes and EPP: CD4, CD8, B, NK, EPP at 3, 6, 9 and 12 months | 3, 6, 9 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) | Minimal residual disease (MRD): before transplant, at day +30 and day +90/100 by flow cytometry, molecular biology and NGS (if available) (ELN 2022 recommendation, Dohner et al Blood 2022) | days +30 and +90 | 
| Comparison of infections after FB2A2 vs CloB2A2: bacterial, viral, parasitic and fungal | Comparison of infections after FB2A2 vs CloB2A2: bacterial, viral, parasitic and fungal between day 0 and day+90/100 | day+90 | 
| Quality of life using the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) | Score of the QLQ-C30 questionnaire, including 30 questions assessing some aspects of the quality of life of cancer patients. The total score ranges from 0 to 100. | Days -7, +30, +90, +180 and +360 | 
| Quality of life using the and FACT-BMT (Functional Assessment of Cancer Therapy - Bone Marrow Transplant)) | Score of the FACT-BMT questionnaire, including 50 questions assessing some aspects of the quality of life of cancer patients. The total score ranges from 0 to 200. | Days -7, +30, +90, +180 and +360 | 
| comparison of the cost of graft hospitalization between the 2 arms | Graft hospitalization cost: Comparison between both groups in terms of length of stay (in days), use of antibiotics (type and length in days) | 2 years | 
| comparison of the cost of graft hospitalization between the 2 arms | Graft hospitalization cost: Comparison between both groups in terms of blood products administered (numbers) | 2 years | 
| health benefit measurement in both treatment arms | General Health State with Euroqol EQ-5D-5L questionnaire at Days -7, 30, 90, 180, 360 and 720; 5 answers are possible. | Days -7, +30, +90, +180, +360 and +720. | 
| Evaluation of economic efficiency of a CloB2A2 compared to a FB2A2 RIC regimen for allo-SCT, from a collective perspective (considering costs to the National Health Insurance system, hospital and patients)with a 24-month time horizon. | Health Economic study: Incremental cost-utility ratio (ICUR, cost per quality-adjusted life year [QALY] gained) and incremental cost-effectiveness ratio (ICER, cost per life year gained), from a collective perspective and with a 24-month time horizon | 2 years | 
| Comparison of Overall survival (OS) between patients in first vs second line therapy and impact of clofarabine vs fludarabine in each sub-group. | Comparison of time from D1 of conditioning to death or last follow-up for survivors | 2 years | 
| Comparison of DFS between patients in first vs second line therapy and impact of clofarabine vs fludarabine in each sub-group. | Comparison of time from day1 of the conditioning to time without death or evidence of relapse or disease progression censored at the date of last follow-up. | 2 years | 
| Comparison of Overall survival (OS) between patients receiving a first vs a second allograft and impact of clofarabine vs fludarabine in each sub-group. | Comparison of time from D1 of conditioning to death or last follow-up for survivors | 2 years | 
| Comparison of DFS between patients receiving a first vs a second allograft and impact of clofarabine vs fludarabine in each sub-group. | Comparison of time from day1 of the conditioning to time without death or evidence of relapse or disease progression censored at the date of last follow-up. | 2 years | 
| Comparison of occurence of Veno-occlusive disease between patients receiving clofarabine vs fludarabine.n day 0 and day+90/100 | Comparison of occurrence of veno-occlusive disease : (Mohty et al, BMT 2016) betwee | day+90 | 
| Safety assessment | Safety assessment: the safety assessment shall be done by collecting all adverse events that occur during the research. All adverse event (except GvHD) shall be graded according to CTC-AE Toxicity Grading Scale (version 5). | 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Acute Myeloid Leukemia, Clofarabine, fludarabine, reduced intensity conditioning regimen, allogeneic stem cells transplantation