Study to Improve OS in 18 to 60 Year-old Patients, Comparing Daunorubicin Versus High Dose Idarubicin Induction Regimens, High Dose Versus Intermediate Dose Cytarabine Consolidation Regimens, and Standard Versus MMF Prophylaxis of GvHD in Allografted Patients in First CR
BIG-1
Phase II/III Randomized Study to Improve Overall Survival in 18 to 60 Year-old Patients, Comparing Daunorubicin Versus High Dose Idarubicin Induction Regimens, High Dose Versus Intermediate Dose Cytarabine Consolidation Regimens, and Standard Versus Mycophenolate Mofetil Prophylaxis of Graft Versus Host Disease in Allografted Patients in First CR : a Backbone InterGroup-1 Trial
1 other identifier
interventional
3,100
1 country
56
Brief Summary
This open label, multicenter phase II/III study with multiple randomization phases at differents stages of AML treatment (induction, consolidation and HSCT where applicable) is designed to improve OS in younger (18 to 60 year-old) patients, with AML risk-adapted patient strategies. Within the intermediate risk AML group, optimal GvHD prophylaxis following allogeneic SCT in first CR, after either myeloablative (MAC) or reduced intensity (RIC) conditioning, will also be evaluated. With an adaptative design, this clinical trial could test up to 3 novel AML agents of interest.
Trial Health
Trial Health Score
Automated assessment based on enrollment pace, timeline, and geographic reach
participants targeted
Target at P75+ for phase_2
Started Jan 2015
Longer than P75 for phase_2
56 active sites
Health score is calculated from publicly available data and should be used for screening purposes only.
Trial Relationships
Click on a node to explore related trials.
Study Timeline
Key milestones and dates
Study Start
First participant enrolled
January 1, 2015
CompletedFirst Submitted
Initial submission to the registry
April 7, 2015
CompletedFirst Posted
Study publicly available on registry
April 15, 2015
CompletedPrimary Completion
Last participant's last visit for primary outcome
July 1, 2025
CompletedStudy Completion
Last participant's last visit for all outcomes
January 1, 2032
ExpectedAugust 7, 2024
August 1, 2024
10.5 years
April 7, 2015
August 6, 2024
Conditions
Outcome Measures
Primary Outcomes (3)
Overall survival
For randomizations R1 (idarubicine vs daunorubicine) and R2 (HDAC vs IDAC)
3 years
Cumulative incidence (CI) of acute Graft versus Host Disease (GvHD) of grade II to IV
For randomization R3 : GvHD prophylaxis study
100 days
Disease free survival
For randomizations R4
18 months
Study Arms (14)
R1-IDA
EXPERIMENTALIdarubicin
R1-DAUNO
ACTIVE COMPARATORDaunorubicin
R2-HDAC
ACTIVE COMPARATORHigh dose cytarabine
R2-IDAC
EXPERIMENTALIntermediate dose cytarabine
R3-MAC-MTX
ACTIVE COMPARATORMethotrexate and mycophenolic acid
R3-MAC-MPA
EXPERIMENTALCyclosporine and mycophenolic acid
R3-RIC-CICLO
ACTIVE COMPARATORCyclosporine
R3-RIC-MPA
EXPERIMENTALCyclosporine and mycophenolic acid
R4-VOS-IDAC
EXPERIMENTALIntermediate dose cytarabine and vosaroxin
R4-IDAC (without VOS)
ACTIVE COMPARATORIntermediate dose cytarabine alone
R4-DEX-HDAC
EXPERIMENTALHigh dose cytarabine and dexamethasone
R4-HDAC (without DEX)
ACTIVE COMPARATORHigh dose cytarabine alone
R4-VEN-IDAC
EXPERIMENTALIntermediate dose cytarabine and venetoclax
R4-IDAC (without VEN)
ACTIVE COMPARATORIntermediate dose cytarabine alone
Interventions
Induction chemotherapy : Idarubicin 9mg/m² /day, from D1 to D5 (IV, 30min) \+ cytarabine 200mg/m²/day from D1 to D7 (IV 24 h) Bone marrow aspirate on D15 : if medullary blasts rate \< 5% → G-CSF (5 μg/kg/day) until hematopoietic recovery (PNN ≥ 1 G/L).
Induction chemotherapy : Daunorubicin 90mg/m²/day, from D1 to D3 (IV, 30min) \+ cytarabine 200mg/m² /day from D1 to D7 (IV 24 h) Bone marrow aspirate on D15 : if medullary blasts rate \< 5% → G-CSF (5 μg/kg/day) until hematopoietic recovery (PNN ≥ 1 G/L).
Consolidation chemotherapy course (s) : -High dose cytarabine: 3g/m² /12h on D1, D3 and D5 For all patients, G-CSF (5 μg/kg/day) : SC or IV (30 min) from D8 until hematopoietic recovery (PNN ≥ 1 G/L) Up to 3 consolidation courses, depending on the patient AML risk group
GvHD prophylaxis post allogeneic SCT : -Cyclosporine : 3 mg/kg /day from D-1 (IV) or 6 mg/kg/day from D-3 (PO). Not to be stopped before D100
GvHD prophylaxis post allogeneic SCT : -15 mg/m² on D+1 then 10 mg/m² on D+3, D+6 and D+11
GvHD prophylaxis post allogeneic SCT : * 720 mg BID from D0 to D+28 for HLA-identical siblings * 720 mg BID from D0 to D+45 for 10/10 HLA allele-matched unrelated donors
Consolidation chemotherapy course (s) : -Intermediate dose cytarabine: 1.5g/m² /12h on D1, D3 and D5 For all patients, G-CSF (5 μg/kg/day) : SC or IV (30 min) from D8 until hematopoietic recovery (PNN ≥ 1 G/L) Up to 3 consolidation courses, depending on the patient AML risk group
Consolidation chemotherapy course (s) : Once RP2D has been determined from the results of the dose selection phase (phase 1), the optimal dose level retained for randomized phase 2 will be one of the following: * 100 mg/d on D1 to D8 (selection phase dose level 1) * or 200 mg/d on D1 to D8 (selection phase dose level 2) * or 400 mg/d on D1 to D8 (selection phase dose level 3) * or 400 mg/d on D1 to D14 (selection phase dose level 4)
Eligibility Criteria
You may qualify if:
- Age ≥ 18 years and \< 61 years
- With a newly diagnosed de novo or secondary type AML (post myelodysplastic syndrome MDS or therapy-related AML)
- No prior treatment for neither AML (with the exception of hydroxyurea), nor MDS (with the exception of EPO)
- ECOG performance status ≤ 3
- Absence of severe uncontrolled infection
- No cardiac contraindications for the use of anthracyclines : decompensated or uncontrolled heart failure, recent myocardial infarction, current signs of cardiac impairment, uncontrolled arrhythmias, LVEF (left ventricular ejection fraction) \< 50%
- Total bilirubin ≤ 2 x upper limit of normal (UNL), ASAT(SGOT) and ALAT (SGPT) ≤ 2.5 X UNL, creatinine \< 150 µmol/l, unless AML-related out of range values
- Genetic mutation testing of the FLT3 (FLT3-ITD ou FLT3-TKD) gene, performed in local or central laboratory
- Use of appropriate methods of contraception:
- for patients treated with Midostaurin:
- women of childbearing potential should use appropriate methods of contaception throughout treatment, and for 5 months post cessation of treatment
- men will need to use condoms during intercourse throughout treatment, and for 5 months post cessation of treatment with Midostaurin
- Patients who are covered by or beneficiaries of a social security system (Social Security or Universal Medical Coverage)
- Patients who have read and understood the information sheet and signed the informed consent form
You may not qualify if:
- Patients with acute promyelocytic leukemia (APL), as confirmed either by t(15;17) or by the presence of PML-RARA fusion transcripts 2.Patients with core binding factor (CBF) AML, as confirmed either by t(8;21), t(16,16) or inv(16), or by fusion transcripts resulting from these cytogenetic abnormalities (RUNX1-RUNX1T1, CBFB-MYH11).
- Patients with secondary AML arising from myeloproliferative disorders previously known according to the 2008 WHO classification 4.Patients with Ph1+ AML or previous Ph1+ disorder (chronic myelogenous leukemia) 5.Severe psychiatric or organic disorder, supposed to be independent from AML, that would contraindicate treatment, including allogeneic HSCT 6.No psychological, familial, social, or geographic reason that would compromise clinical follow up 7.History of uncontrolled cancer for the last 2 years, with the exception of basal cell carcinoma or carcinoma in situ of the cervix 8.Uncontrolled severe infection 9.Patients with positive serology for HIV-1 and -2, or HTLV -1 and -2, or active hepatitis virus B or C infection 10.Pregnant or lactating women 11.Legal incapacity (patients under tutorship, curatorship or judicial protection)
- \------------------------------------------
- For randomization R4-VOS (post-induction/salvage) :
- Patients enrolled in the BIG-1 trial at diagnosis
- Patient presenting with AML in first CR or CRp/CRi after induction or one cycle of salvage therapy (confirmed in the 15 days preceding R4-VOS)
- Favorable or intermediate risk AML patients, as stratified with BIG-1 prognostic classification
- Patients randomized to R2-IDAC arm (intermediate dose cytarabine)
- ECOG performance status ≤ 2
- Left ventricular ejection fraction (LVEF) at least 40% by multiple gated acquisition (MUGA) scan or echocardiogram (ECHO)
- Local clinical laboratory values as follows:
- o Serum creatinine ≤ 2.0 mg/dL
- o Total bilirubin ≤ 1.5 X the upper limit of normal (ULN)
- Aspartate aminotransferase (AST) ≤ 2.5 X ULN
- Alanine aminotransferase (ALT) ≤ 2.5 X ULN
- +49 more criteria
Contact the study team to confirm eligibility.
Sponsors & Collaborators
Study Sites (56)
CH Amiens Hôpital Sud
Amiens, France
CHU Angers
Angers, 49100, France
CH Victor Dupouy
Argenteuil, France
Centre Hospitalier de la Côte Basque
Bayonne, France
Hôpital Jean Minjoz
Besançon, France
CH Beziers
Béziers, France
Hôpital Avicenne
Bobigny, France
CH Bordeaux
Bordeaux, France
Hôpital du Dr Duchenne
Boulogne-sur-Mer, France
Hôpital Morvan
Brest, France
CH Caen
Caen, France
Clinique du parc
Castelnau-le-Lez, 34170, France
Centre Hospitalier René Dubos
Cergy-Pontoise, France
HIA Percy
Clamart, France
CHU Estaing
Clermont-Ferrand, France
Centre Hospitalier Sud Francilien
Corbeil-Essonnes, France
Hôpital Henri Mondor
Créteil, France
CHU de Dijon
Dijon, France
CH Dunkerque
Dunkirk, France
Hôpital Michallon
Grenoble, France
CH Versailles
Le Chesnay, France
CH Lens
Lens, France
CHRU de Lille, Hôpital Huriez
Lille, France
Hôpital St Vincent de Paul
Lille, France
CHU de Limoges
Limoges, France
Centre Leon Berard (CLB)
Lyon, France
CH Lyon Sud
Lyon, France
Marseille La Conception
Marseille, 13005, France
Institut Paoli Calmettes
Marseille, France
CH Meaux
Meaux, France
CHR Metz Thionville_Hôpital de Mercy
Metz, France
Hôpital Saint Eloi
Montpellier, France
CH Mulhouse
Mulhouse, France
CH Hôtel Dieu
Nantes, France
Centre Antoine Lacassagne
Nice, France
CHU Nice
Nice, France
CHRU de Nîmes
Nîmes, France
Hôpital Cochin
Paris, France
Hôpital La Pitié Salpêtrière
Paris, France
Hôpital Necker Enfants Malades
Paris, France
Hôpital Saint Antoine
Paris, France
Hôpital St Louis
Paris, France
Centre Hospitalier Saint Jean
Perpignan, France
CHU de Poitiers
Poitiers, France
Hôpital Robert Debré
Reims, France
CH Pontchaillou
Rennes, France
Hopital Victor Provo
Roubaix, France
Centre Henri Becquerel
Rouen, France
Hôpital René Huguenin
Saint-Cloud, France
Institut de Cancérologie Lucien Neuwirth
Saint-Priest-en-Jarez, France
Hôpital Hautepierre
Strasbourg, France
IUCT Toulouse
Toulouse, France
CHU Bretonneau
Tours, France
CH Valenciennes
Valenciennes, France
Hôpitaux de Brabois_CHU Nancy
Vandœuvre-lès-Nancy, France
Institut de Cancérologie Gustave Roussy
Villejuif, France
Related Publications (1)
Hunault M, Pautas C, Bertoli S, Dumas PY, Raffoux E, Hospital MA, Marchand T, Heiblig M, Chantepie S, Carre M, Peterlin P, Gallego-Hernanz MP, Lemasle E, Guieze R, Simand C, Turlure P, Huynh A, Leguay T, Devillier R, Quoc SN, Duployez N, Luquet I, Penther D, Celli-Lebras K, Mineur A, Raus N, Gardin C, Socie G, Cahn JY, Ifrah N, Vey N, de Latour RP, Delabesse E, Preudhomme C, Hamel JF, Pigneux A, Recher C, Dombret H. Intermediate-Dose Cytarabine as Postinduction AML Therapy. NEJM Evid. 2025 Jul;4(7):EVIDoa2400326. doi: 10.1056/EVIDoa2400326. Epub 2025 Jun 24.
PMID: 40552969DERIVED
MeSH Terms
Conditions
Interventions
Condition Hierarchy (Ancestors)
Intervention Hierarchy (Ancestors)
Central Study Contacts
Study Design
- Study Type
- interventional
- Phase
- phase 2
- Allocation
- RANDOMIZED
- Masking
- NONE
- Purpose
- TREATMENT
- Intervention Model
- PARALLEL
- Sponsor Type
- OTHER GOV
- Responsible Party
- SPONSOR
Study Record Dates
First Submitted
April 7, 2015
First Posted
April 15, 2015
Study Start
January 1, 2015
Primary Completion
July 1, 2025
Study Completion (Estimated)
January 1, 2032
Last Updated
August 7, 2024
Record last verified: 2024-08