Clinical trial NCT05917405: 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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Acute Myeloid Leukemia in Remission
Keywords: Acute Myeloid Leukemia
Clofarabine
fludarabine
reduced intensity conditioning regimen
allogeneic stem cells transplantation
Lead sponsor: Nantes University Hospital
Sponsor class: OTHER
First posted: 2023-06-23
Enrollment: 302
Sex: ALL
Minimum age (years): 18
Maximum age (years): 99
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.


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%)
* 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.

Primary outcomes:
measure: To compare 2-year OS between patients with AML in complete remission receiving either a CloB2A2 or a FB2A2 RIC regimen for allo-SCT.
timeFrame: 2 years
Secondary outcomes:
measure: 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
timeFrame: day +30/42 and 2 years
measure: To compare between AML patients in complete remission receiving either a CloB2A2 or a FB2A2 RIC regimen for allo-SCT: Neutrophils and platelet recoveries
timeFrame: 2 years
measure: To compare between AML patients in complete remission receiving either a CloB2A2 or a FB2A2 RIC regimen for allo-SCT: 2-year DFS
timeFrame: 2 years
measure: To compare between AML patients in complete remission receiving either a CloB2A2 or a FB2A2 RIC regimen for allo-SCT:-2-year relapse incidence
timeFrame: 2 years
measure: To compare between AML patients in complete remission receiving either a CloB2A2 or a FB2A2 RIC regimen for allo-SCT:2-year NRM
timeFrame: 2 years
measure: 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)
timeFrame: Day 90 and 2 years
measure: 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)
timeFrame: 2 years
measure: To compare between AML patients in complete remission receiving either a CloB2A2 or a FB2A2 RIC regimen for allo SCT:Chimerism
timeFrame: days +30, +60, +90
measure: To compare between AML patients in complete remission receiving either a CloB2A2 or a FB2A2 RIC regimen for allo- SCT:Immune reconstitution
timeFrame: 3, 6, 9 and 12 months
measure: To compare between AML patients in complete remission receiving either a CloB2A2 or a FB2A2 RIC regimen for allo- SCT: Minimal residual disease (MRD)
timeFrame: days +30 and +90
measure: Comparison of infections after FB2A2 vs CloB2A2: bacterial, viral, parasitic and fungal
timeFrame: day+90
measure: Quality of life using the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30)
timeFrame: Days -7, +30, +90, +180 and +360
measure: Quality of life using the and FACT-BMT (Functional Assessment of Cancer Therapy - Bone Marrow Transplant))
timeFrame: Days -7, +30, +90, +180 and +360
measure: comparison of the cost of graft hospitalization between the 2 arms
timeFrame: 2 years
measure: comparison of the cost of graft hospitalization between the 2 arms
timeFrame: 2 years
measure: health benefit measurement in both treatment arms
timeFrame: Days -7, +30, +90, +180, +360 and +720.
measure: 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.
timeFrame: 2 years
measure: Comparison of Overall survival (OS) between patients in first vs second line therapy and impact of clofarabine vs fludarabine in each sub-group.
timeFrame: 2 years
measure: Comparison of DFS between patients in first vs second line therapy and impact of clofarabine vs fludarabine in each sub-group.
timeFrame: 2 years
measure: Comparison of Overall survival (OS) between patients receiving a first vs a second allograft and impact of clofarabine vs fludarabine in each sub-group.
timeFrame: 2 years
measure: Comparison of DFS between patients receiving a first vs a second allograft and impact of clofarabine vs fludarabine in each sub-group.
timeFrame: 2 years
measure: Comparison of occurence of Veno-occlusive disease between patients receiving clofarabine vs fludarabine.n day 0 and day+90/100
timeFrame: day+90
measure: Safety assessment
timeFrame: 2 years
Other outcomes:
Locations:
city: Nantes
country: France
facility: CHU de Nantes
state: Loire Atlantique
city: Amiens
country: France
facility: CHU Amiens
city: Angers
country: France
facility: CHU Angers
city: Besançon
country: France
facility: CHU Besançon
city: Bordeaux
country: France
facility: CHU Bordeaux
city: Brest
country: France
facility: CHU Brest
city: Caen
country: France
facility: CRLC Caen
city: Clermont-Ferrand
country: France
facility: CHU Clermont-Ferrand
city: Créteil
country: France
facility: APHP Créteil
city: Grenoble
country: France
facility: CHU Grenoble
city: Lille
country: France
facility: CHRU Lille
city: Limoges
country: France
facility: CHU Limoges
city: Lyon
country: France
facility: CHU Lyon
city: Marseille
country: France
facility: Institut Paoli Calmettes
city: Montpellier
country: France
facility: CHU Montpellier
city: Nancy
country: France
facility: CHRU Nancy
city: Paris
country: France
facility: CHU Paris St-Louis
city: Paris
country: France
facility: Pitie-Salpetriere, APHP
city: Paris
country: France
facility: St-Antoine, APHP
city: Poitiers
country: France
facility: CHU Poitiers
city: Rennes
country: France
facility: CHU Rennes
city: Saint-Étienne
country: France
facility: CHU St-Etienne
city: Toulouse
country: France
facility: CRLC Toulouse
Study officials:
affiliation: Nantes University Hospital
name: patrice CHEVALLIER, Pr
role: PRINCIPAL_INVESTIGATOR
References: