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

Registration Number
NCT05917405
Lead Sponsor
Nantes University Hospital
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 compar...

Detailed Description

Not available

Recruitment & Eligibility

Status
RECRUITING
Sex
All
Target Recruitment
302
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.
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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.
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Study & Design

Study Type
INTERVENTIONAL
Study Design
PARALLEL
Arm && Interventions
GroupInterventionDescription
Experimental: CloB2 armATG* 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
Experimental: CloB2 armBusulfan* 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
Experimental: CloB2 armClofarabine* 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
Comparator: FB2A2 armFludarabine* 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)
Comparator: FB2A2 armBusulfan* 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)
Comparator: FB2A2 armATG* 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)
Primary Outcome Measures
NameTimeMethod
To compare 2-year OS between patients with AML in complete remission receiving either a CloB2A2 or a FB2A2 RIC regimen for allo-SCT.2 years

OS is defined as the time from day 1 of conditioning to death or last follow-up for survivors.

Secondary Outcome Measures
NameTimeMethod
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 failureday +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)

To compare between AML patients in complete remission receiving either a CloB2A2 or a FB2A2 RIC regimen for allo-SCT:2-year NRM2 years

NRM: death from any cause without previous relapse or progression from day 1 of the conditioning

To compare between AML patients in complete remission receiving either a CloB2A2 or a FB2A2 RIC regimen for allo- SCT: Minimal residual disease (MRD)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)

Comparison of infections after FB2A2 vs CloB2A2: bacterial, viral, parasitic and fungalday+90

Comparison of infections after FB2A2 vs CloB2A2: bacterial, viral, parasitic and fungal between day 0 and day+90/100

Quality of life using the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30)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.

health benefit measurement in both treatment armsDays -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.

To compare between AML patients in complete remission receiving either a CloB2A2 or a FB2A2 RIC regimen for allo-SCT: Neutrophils and platelet recoveries2 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

To compare between AML patients in complete remission receiving either a CloB2A2 or a FB2A2 RIC regimen for allo-SCT:-2-year relapse incidence2 years

Relapse: any event related to progression or re-occurrence of the disease from day 1 of the conditioning.

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)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

To compare between AML patients in complete remission receiving either a CloB2A2 or a FB2A2 RIC regimen for allo SCT:Chimerismdays +30, +60, +90

Chimerism: peripheral blood and CD3 T cells by molecular markers at days +30, +60, +90/100

To compare between AML patients in complete remission receiving either a CloB2A2 or a FB2A2 RIC regimen for allo-SCT: 2-year DFS2 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.

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)Day 90 and 2 years

* Acute GVHD: NIH criteria

* Chronic GVHD: NIH criteria

To compare between AML patients in complete remission receiving either a CloB2A2 or a FB2A2 RIC regimen for allo- SCT:Immune reconstitution3, 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

Quality of life using the and FACT-BMT (Functional Assessment of Cancer Therapy - Bone Marrow Transplant))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.

comparison of the cost of graft hospitalization between the 2 arms2 years

Graft hospitalization cost: Comparison between both groups in terms of blood products administered (numbers)

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.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

Comparison of Overall survival (OS) between patients in first vs second line therapy and impact of clofarabine vs fludarabine in each sub-group.2 years

Comparison of time from D1 of conditioning to death or last follow-up for survivors

Comparison of occurence of Veno-occlusive disease between patients receiving clofarabine vs fludarabine.n day 0 and day+90/100day+90

Comparison of occurrence of veno-occlusive disease : (Mohty et al, BMT 2016) betwee

Safety assessment2 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).

Comparison of DFS between patients in first vs second line therapy and impact of clofarabine vs fludarabine in each sub-group.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.

Comparison of Overall survival (OS) between patients receiving a first vs a second allograft and impact of clofarabine vs fludarabine in each sub-group.2 years

Comparison of time from D1 of conditioning to death or last follow-up for survivors

Comparison of DFS between patients receiving a first vs a second allograft and impact of clofarabine vs fludarabine in each sub-group.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.

Trial Locations

Locations (23)

CRLC Caen

🇫🇷

Caen, France

CHU Limoges

🇫🇷

Limoges, France

CHU Besançon

🇫🇷

Besançon, France

CHU Bordeaux

🇫🇷

Bordeaux, France

CHU Angers

🇫🇷

Angers, France

CHU Brest

🇫🇷

Brest, France

CHU Clermont-Ferrand

🇫🇷

Clermont-Ferrand, France

CHU Grenoble

🇫🇷

Grenoble, France

CHRU Lille

🇫🇷

Lille, France

Institut Paoli Calmettes

🇫🇷

Marseille, France

CHU Montpellier

🇫🇷

Montpellier, France

CHRU Nancy

🇫🇷

Nancy, France

Pitie-Salpetriere, APHP

🇫🇷

Paris, France

CHU de Nantes

🇫🇷

Nantes, Loire Atlantique, France

CHU Amiens

🇫🇷

Amiens, France

APHP Créteil

🇫🇷

Créteil, France

CHU Lyon

🇫🇷

Lyon, France

CHU Paris St-Louis

🇫🇷

Paris, France

St-Antoine, APHP

🇫🇷

Paris, France

CHU Poitiers

🇫🇷

Poitiers, France

CHU Rennes

🇫🇷

Rennes, France

CRLC Toulouse

🇫🇷

Toulouse, France

CHU St-Etienne

🇫🇷

Saint-Étienne, France

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