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

November 13, 2023 updated by: Nantes University Hospital

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

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.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Study Type

Interventional

Enrollment (Estimated)

302

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • France
      • Amiens, France
      • Angers, France
      • Besançon, France
      • Bordeaux, France
      • Brest, France
      • Caen, France
      • Clermont-Ferrand, France
      • Créteil, France
        • Not yet recruiting
        • APHP Créteil
        • Contact:
      • Grenoble, France
      • Lille, France
      • Limoges, France
      • Lyon, France
      • Marseille, France
        • Not yet recruiting
        • Institut Paoli Calmettes
        • Contact:
      • Montpellier, France
      • Nancy, France
        • Not yet recruiting
        • CHRU Nancy
        • Contact:
      • Paris, France
        • Not yet recruiting
        • CHU Paris St-Louis
        • Contact:
      • Paris, France
      • Paris, France
        • Not yet recruiting
        • St-Antoine, APHP
        • Contact:
      • Poitiers, France
      • Rennes, France
      • Saint-Étienne, France
      • Toulouse, France
    • Loire Atlantique
      • Nantes, Loire Atlantique, France, 44000

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Experimental: CloB2 arm
  • 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
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)
Active Comparator: Comparator: FB2A2 arm
  • 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: 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: Fludarabine
30 mg/m2/day IV fludarabine for 5 days (day-6 to day-2)

What is the study measuring?

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.
Time Frame: 2 years
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
Time Frame: day +30/42 and 2 years
  • 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
Time Frame: 2 years
  • 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
Time Frame: 2 years
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
Time Frame: 2 years
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
Time Frame: 2 years
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)
Time Frame: Day 90 and 2 years
  • 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)
Time Frame: 2 years
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
Time Frame: days +30, +60, +90
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
Time Frame: 3, 6, 9 and 12 months
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)
Time Frame: days +30 and +90
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
Time Frame: day+90
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)
Time Frame: Days -7, +30, +90, +180 and +360
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))
Time Frame: Days -7, +30, +90, +180 and +360
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
Time Frame: 2 years
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
Time Frame: 2 years
Graft hospitalization cost: Comparison between both groups in terms of blood products administered (numbers)
2 years
health benefit measurement in both treatment arms
Time Frame: Days -7, +30, +90, +180, +360 and +720.
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.
Time Frame: 2 years
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.
Time Frame: 2 years
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.
Time Frame: 2 years
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.
Time Frame: 2 years
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.
Time Frame: 2 years
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
Time Frame: day+90
Comparison of occurrence of veno-occlusive disease : (Mohty et al, BMT 2016) betwee
day+90
Safety assessment
Time Frame: 2 years
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

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Nantes University Hospital

Investigators

  • Principal Investigator: patrice CHEVALLIER, Pr, Nantes University Hospital

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

September 14, 2023

Primary Completion (Estimated)

September 14, 2028

Study Completion (Estimated)

September 14, 2028

Study Registration Dates

First Submitted

May 16, 2023

First Submitted That Met QC Criteria

June 15, 2023

First Posted (Actual)

June 23, 2023

Study Record Updates

Last Update Posted (Actual)

November 15, 2023

Last Update Submitted That Met QC Criteria

November 13, 2023

Last Verified

November 1, 2023

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • RC22_0524

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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