FLUCLORIC - Randomized multicentric Phase III study comparing the efficacy of two reduced intensity conditioning regimens (clofarabine/busulfan versus fludarabine/busulfan) in adults with acute myeloid leukemia and eligible to allogeneic stem cell transplantation: a SFGM-TC study

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Centre Hospitalier Universitaire De Nantes

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Hemic and Lymphatic Diseases [C15]

Trial duration

14 Sep 2023 → ongoing

Decision date (initial)

2023-04-27

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy

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

Secondary objectives 21

1. 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
2. To compare between AML patients in complete remission receiving either a CloB2A2 or a FB2A2 RIC regimen for allo-SCT: Neutrophils and platelet recoveries
3. To compare between AML patients in complete remission receiving either a CloB2A2 or a FB2A2 RIC regimen for allo-SCT: 2-year DFS
4. To compare between AML patients in complete remission receiving either a CloB2A2 or a FB2A2 RIC regimen for allo-SCT:-2-year relapse incidence
5. To compare between AML patients in complete remission receiving either a CloB2A2 or a FB2A2 RIC regimen for allo-SCT:2-year NRM
6. 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)
7. 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)
8. To compare between AML patients in complete remission receiving either a CloB2A2 or a FB2A2 RIC regimen for allo-SCT:Chimerism
9. To compare between AML patients in complete remission receiving either a CloB2A2 or a FB2A2 RIC regimen for allo-SCT:Immune reconstitution
10. To compare between AML patients in complete remission receiving either a CloB2A2 or a FB2A2 RIC regimen for allo-SCT: Minimal residual disease (MRD)
11. Outcomes according to FB2 vs CloB2, to ELN classification: good, intermediate, high-risk sub-groups; to molecular markers: FLT3-ITD vs -, NPM1+ vs –, and to minimal residual disease by flow cytometry: + vs – before transplant
12. Comparison of infections after FB2A2 vs CloB2A2: bacterial, viral, parasitic and fungal
13. Quality of Life (QoL) in both treatment arms
14. Graft hospitalization: Comparison between both groups in terms of length of stay, use of antibiotics and blood products
15. General Health State in both treatment arms
16. Health Economic study: Evaluation of economic efficiency of a CloB2A2 compared to a FB2A2 RIC regimen for allo-SCT in patients with AML, from a collective perspective (considering costs to the National Health Insurance (NHI) system, hospital and patients) and with a 24-month time horizon. Two analyses will be performed: a cost-utility analysis (CUA) and a cost-effectiveness analysis (CEA). The effectiveness of the two compared strategies will be assessed in terms of potential changes in survival weighted by quality of life (CUA) and in terms of survival (CEA), respectively
17. Comparison of outcomes between patients in first vs second line therapy and impact of clofarabine vs fludarabine in each sub-group.
18. Comparison of outcomes between patients receiving a first vs a second allograft and impact of clofarabine vs fludarabine in each sub-group.
19. better understand the superiority of clofarabine vs fludarabine in terms of relapse decrease after allotransplant in AML
20. To compare between AML patients in complete remission receiving either a CloB2A2 or a FB2A2 RIC regimen for allo-SCT: Veno-occlusive disease
21. Safety assessment

Conditions and MedDRA coding

acute myeloid leukemia

Study design 1 period

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 11

1. Age ≥ 18 years’ old
2. De novo or secondary AML in complete cytological remission at time of transplant (bone marrow blast count < 5%) or MDS/LAM with bone marrow blast count ≤ 5%
3. Patients in first or second line therapy are allowed
4. Patient eligible to a RIC regimen : : patients aged ≥ 60 year old or < 60 year old with co-morbidity(ies).
5. Patient with a related or an unrelated matched donor
6. Graft using only peripheral blood stem cells
7. Performance status ECOG 0 - 2
8. Who provide their written informed consent
9. Previous allograft allowed
10. Affiliated with French social security system or beneficiary from such system
11. 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 15

1. Pro-myelocytic leukemia
2. Creatinine clearance < 50 ml/min (evaluated by MDRD or CKDEPI)
3. Serum bilirubine > 30 mmol/l, Cytolysis >5 the upper limit range
4. 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
5. Any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule
6. Participation to another interventional study during the last month or expected participation to another interventional study during participation to the FLUCLORIC study
7. Patient eligible to a myeloablative conditioning regimen
8. Patient with haploidentical, mismatched unrelated donor or umbilical cord blood
9. Pregnant or breastfeeding woman or patient refusing contraceptive mesures
10. HIV positive
11. Active Hepatitis B or C
12. Left ventricular ejection fraction < 50%
13. DLCOc <40%
14. Uncontrolled infection
15. Uncontrolled haemolytic anaemia

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

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

Secondary endpoints 21

1. -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)
2. -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
3. DFS: time from day 1 of the conditioning to time without death or evidence of relapse or disease progression censored at the date of last follow-up.
4. Relapse: any event related to progression or re-occurrence of the disease from day 1 of the conditioning
5. NRM: death from any cause without previous relapse or progression from day 1 of the conditioning
6. Acute GVHD: NIH criteria
7. Chronic GVHD: NIH criteria
8. 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
9. Chimerism: peripheral blood and CD3 T cells by molecular markers at days +30, +60, +90/100
10. Immune reconstitution: Immunophenotype of PB lymphocytes and EPP: CD4, CD8, B, NK, EPP at 3, 6, 9 and 12 months
11. Minimal residual disease (MRD): before transplant, at day +30/60 and dayd+90/100 by flow cytometry, molecular biology and NGS (if available) (ELN 2022 recommendation, Dohner et al Blood 2022)
12. Comparison of infections after FB2A2 vs CloB2A2: bacterial, viral, parasitic and fungal between day 0 and day+90/100
13. Quality of life: EORTC QLQ-C30 (European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30) and FACT-BMT (Functional Assessment of Cancer Therapy - Bone Marrow Transplant). at D-7, D30, D90, D180 and D360
14. Graft hospitalization: Comparison between both groups in terms of length of stay (in days), use of antibiotics (type and length in days) and blood products (numbers)
15. General Health State with Euroqol EQ-5D-5L questionnaire at D-7, D30, D90, D180, D360 and D720.
16. 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
17. Comparison of outcomes betwwen patients in first vs second line therapy and impact of clofarabine vs fludaribine in each sub-group: OS, DFS, RI, NRM
18. Comparison of outcomes between patients receiving a first vs a second allograft and impact of clofarabine vs fludarabine in each sub-group: OS, DFS, RI, NRM
19. dosage of leukemics blasts at diagnosis or at relapse and description of immune sub-population reconstitution post allograft (at inclusion, months 3, 6, 9 and 12).
20. Comparison of occurrence of veno-occlusive disease : (Mohty et al, BMT 2016) between day 0 and day+90/100
21. 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).

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Comparator 1

Auxiliary 6

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Centre Hospitalier Universitaire De Nantes

Sponsor organisation

Centre Hospitalier Universitaire De Nantes

Address

5 Allee De L Ile Gloriette, Cs 69301 Cs 69301

City

Nantes Cedex 1

Postcode

44093

Country

France

Scientific contact point

Organisation

Centre Hospitalier Universitaire De Nantes

Contact name

Pr Patrice CHEVALLIER

Public contact point

Organisation

Centre Hospitalier Universitaire De Nantes

Contact name

Marion GAUTIER

Locations

1 EU/EEA country · 23 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 14 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

2 submissions — initial application plus substantial / non-substantial modifications