Informations générales (source: ClinicalTrials.gov)
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 (BIG-1)
Interventional
Phase 2/Phase 3
University Hospital, Angers (Voir sur ClinicalTrials)
janvier 2015
janvier 2032
08 août 2024
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.
Etablissements
| Les établissements d'Île-de-France ayant mis à jour leurs données Origine et niveau de fiabilité des données | |||||
|---|---|---|---|---|---|
| CLCC INSTITUT CURIE | 04/06/2024 14:01:40 | Contact (sur clinicalTrials) | |||
| CLCC INSTITUT GUSTAVE ROUSSY | Jean-Baptiste MICOL | 05/06/2024 10:29:18 | Contacter | ||
| CLCC RENE HUGUENIN INSTITUT CURIE | 04/12/2024 12:44:08 | Contact (sur clinicalTrials) | |||
| HOPITAL NOVO | VAIDA | 04/12/2024 13:04:44 | Contacter | ||
| Les établissements d'Île-de-France dont les données sont issues de ClinicalTrials.gov Origine et niveau de fiabilité des données | |||||
| AP-HP - Hôpital Avicenne | Claude Gardin | Contact (sur clinicalTrials) | |||
| AP-HP - Hôpital Cochin | Didier Bouscary | Contact (sur clinicalTrials) | |||
| AP-HP - Hôpital Necker-Enfants Malades | Felipe Suarez | Contact (sur clinicalTrials) | |||
| AP-HP - Hôpital Saint Antoine | Ollivier Legrand | Contact (sur clinicalTrials) | |||
| CENTRE HOSPITALIER SUD FRANCILIEN | Celia Salanoubat | Contact (sur clinicalTrials) | |||
| CH VICTOR DUPOUY ARGENTEUIL | Ahmad Al Jijakli | Contact (sur clinicalTrials) | |||
| CH DE VERSAILLES SITE ANDRE MIGNOT | Philippe Rousselot | Contact (sur clinicalTrials) | |||
| Les établissements hors Île-de-France dont les données sont issues de ClinicalTrials.gov Origine et niveau de fiabilité des données | |||||
| Centre Hospitalier de la Côte Basque - Bayonne - France | Anne Banos | Contact (sur clinicalTrials) | |||
| CH Amiens Hôpital Sud - Amiens - France | Jean-Pierre Marolleau | Contact (sur clinicalTrials) | |||
| CH Dunkerque - Dunkerque - France | Maxime Bemba | Contact (sur clinicalTrials) | |||
| CH Hôtel Dieu - Nantes - France | Pierre Peterlin | Contact (sur clinicalTrials) | |||
| CH Lens - Lens - France | Laure STALNIKIEWICZ | Contact (sur clinicalTrials) | |||
| CH Lyon Sud - Lyon - France | Xavier Thomas | Contact (sur clinicalTrials) | |||
| CH Valenciennes - Valenciennes - France | Jose Fernandes | Contact (sur clinicalTrials) | |||
| CHR Metz Thionville_Hôpital de Mercy - Metz - France | Veronique Dorvaux | Contact (sur clinicalTrials) | |||
| CHRU de Lille, Hôpital Huriez - Lille - France | Bruno Quesnel | Contact (sur clinicalTrials) | |||
| CHRU de Nîmes - Nîmes - France | Eric Jourdan | Contact (sur clinicalTrials) | |||
| CHU de Limoges - Limoges - France | Pascal Turlure | Contact (sur clinicalTrials) | |||
| CHU de Poitiers - Poitiers - France | Maria Pilar Gallego-Hernanz | Contact (sur clinicalTrials) | |||
| Les établissements sans correspondance certaine dans le répertoire FINESS dont les données sont issues de ClinicalTrials.gov Origine et niveau de fiabilité des données | |||||
| Centre Antoine Lacassagne - Nice - France | Lauris Gastaud | Contact (sur clinicalTrials) | |||
| Centre Hospitalier Saint Jean - Perpignan - France | Laurence Sahnes | Contact (sur clinicalTrials) | |||
| Centre Leon Berard (CLB) - Lyon - France | Amine Belhabri | Contact (sur clinicalTrials) | |||
| CH Beziers - Beziers - France | Alain Saad | Contact (sur clinicalTrials) | |||
| CH Bordeaux - Bordeaux - France | Arnaud Pigneux | Contact (sur clinicalTrials) | |||
| CH Caen - Caen - France | Sylvain Chantepie | Contact (sur clinicalTrials) | |||
| CH Meaux - Meaux - France | Jamilé Frayfer | Contact (sur clinicalTrials) | |||
| CH Mulhouse - Mulhouse - France | Mario Ojeda-Uribe | Contact (sur clinicalTrials) | |||
| CH Pontchaillou - Rennes - France | Marc Bernard | Contact (sur clinicalTrials) | |||
| CHU Angers - 49100 - Angers - France | Mathilde Hunault | Contact (sur clinicalTrials) | |||
| CHU Bretonneau - Tours - France | Emmanuel Gyan | Contact (sur clinicalTrials) | |||
| CHU de Dijon - Dijon - France | Denis Caillot | Contact (sur clinicalTrials) | |||
| CHU Estaing - Clermont-Ferrand - France | Aurelie Ravinet | Contact (sur clinicalTrials) | |||
| CHU Nice - Nice - France | Thomas Cluzeau | Contact (sur clinicalTrials) | |||
| Clinique du parc - 34170 - Castelnau Le lez - France | Contact (sur clinicalTrials) | ||||
| HIA Percy - Clamart - France | Jean-Valère Malfuson | Contact (sur clinicalTrials) | |||
| Hôpital du Dr Duchenne - Boulogne sur Mer - France | Bachra Choufi | Contact (sur clinicalTrials) | |||
| Hôpital Hautepierre - Strasbourg - France | Bruno Lioure | Contact (sur clinicalTrials) | |||
| Hôpital Henri Mondor - Créteil - France | Contact (sur clinicalTrials) | ||||
| Hôpital Jean Minjoz - Besancon - France | Fabrice Larosa | Contact (sur clinicalTrials) | |||
| Hôpital La Pitié Salpêtrière - Paris - France | Madalina Uzunov | Contact (sur clinicalTrials) | |||
| Hôpital Michallon - Grenoble - France | Jean-Yves Cahn | Contact (sur clinicalTrials) | |||
| Hôpital Morvan - Brest - France | Gaelle Guillerm | Contact (sur clinicalTrials) | |||
| Hôpital René Huguenin - St Cloud - France | Jacques Vargaftig | Contact (sur clinicalTrials) | |||
| Hôpital Robert Debré - Reims - France | Chantal Himberlin | Contact (sur clinicalTrials) | |||
| Hôpital Saint Eloi - Montpellier - France | Yosr Hicheri | Contact (sur clinicalTrials) | |||
| Hôpital St Louis - Paris - France | Emmanuel Raffoux | Contact (sur clinicalTrials) | |||
| Hôpital St Vincent de Paul - Lille - France | Nathalie Cambier | Contact (sur clinicalTrials) | |||
| Hopital Victor Provo - Roubaix - France | Isabelle Plantier | Contact (sur clinicalTrials) | |||
| Hôpitaux de Brabois_CHU Nancy - Vandoeuvre-les-Nancy - France | Gabrielle Roth-Guepin | Contact (sur clinicalTrials) | |||
| Institut de Cancérologie Lucien Neuwirth - St Priest en Jarez - France | Emmanuelle Tavernier | Contact (sur clinicalTrials) | |||
| Institut Paoli Calmettes - Marseille - France | Norbert Vey | Contact (sur clinicalTrials) | |||
| IUCT Toulouse - Toulouse - France | Christian Recher | Contact (sur clinicalTrials) | |||
| Marseille La Conception - 13005 - Marseille - France | Régis COSTELLO, PD | Contact (sur clinicalTrials) | |||
Critères
Tous
Inclusion Criteria (at diagnosis) :
1. Age ≥ 18 years and < 61 years
2. With a newly diagnosed de novo or secondary type AML (post myelodysplastic syndrome
MDS or therapy-related AML)
3. No prior treatment for neither AML (with the exception of hydroxyurea), nor MDS
(with the exception of EPO)
4. ECOG performance status ≤ 3
5. Absence of severe uncontrolled infection
6. 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%
7. 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
8. Genetic mutation testing of the FLT3 (FLT3-ITD ou FLT3-TKD) gene, performed in local
or central laboratory
9. 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
10. Patients who are covered by or beneficiaries of a social security system (Social
Security or Universal Medical Coverage)
11. Patients who have read and understood the information sheet and signed the informed
consent form
Exclusion criteria (at diagnosis) :
1.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).
3.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) :
Inclusion criteria
1. Patients enrolled in the BIG-1 trial at diagnosis
2. 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)
3. Favorable or intermediate risk AML patients, as stratified with BIG-1 prognostic
classification
4. Patients randomized to R2-IDAC arm (intermediate dose cytarabine)
5. ECOG performance status ≤ 2
6. Left ventricular ejection fraction (LVEF) at least 40% by multiple gated acquisition
(MUGA) scan or echocardiogram (ECHO)
7. 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
8. Signed written informed consent for vosaroxin study (R4-VOS)
9. Women of childbearing potential must have a negative pregnancy test within 8 days
before randomization R4-VOS and commit to the use of effective contraception during
the period of treatment and up to 36 days after vosaroxin has been stopped. Men must
use effective contraception during the treatment period and up to 96 days after
vosaroxin has been stopped.
Exclusion criteria
1.Patients classified in the unfavorable risk group according to the BIG-1 protocol
classification 2.Complete remission is not attained (CR, CRp/CRi) after induction and/or
salvage therapy 3.Positive pregnancy test 4.Severe uncontrolled infection such as sepsis,
or multiple organ dysfunction syndrome, uncontrolled fever 5.Documented uncontrolled
fungal infection (positive blood test and cultures) 6.History of myocardial infarction,
unstable angina, cerebrovascular accident (CVA) or transient ischemic attack (TIA) in the
3 months before randomization 7.Patient under hemodialysis (HD) or peritoneal dialysis
(PD)
For randomization R4-DEX (post-induction/salvage) :
Inclusion criteria
1. Patients enrolled in the BIG-1 trial at diagnosis
2. 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-DEX)
3. Favorable or intermediate risk AML patients, as stratified with BIG-1 prognostic
classification
4. ECOG performance status ≤ 2
5. Local clinical laboratory values as follows:
- Serum creatinine ≤ 150 µmol/L
- 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
6. Signed written informed consent for dexamethasone study (R4-DEX)
Exclusion criteria
1.Severe uncontrolled infection such as sepsis, or multiple organ dysfunction syndrome,
uncontrolled fever 2.Documented uncontrolled fungal infection (positive blood test and
cultures 3.History of myocardial infarction, unstable angina, cerebrovascular accident
(CVA) or transient ischemic attack (TIA) in the 3 months before randomization 4.Patient
under hemodialysis (HD) or peritoneal dialysis (PD)
For randomization R4-VEN (post-induction/salvage) :
Inclusion criteria
1. Age 18 - 60 years at inclusion in BIG-1 protocol
2. diagnosis of AML according to WHO classification de novo or secondary to
myelodysplastic syndrome (myelodysplastic syndrome must not have been treated except
by ESA, Lenalidomide or non-chemotherapy) or therapy-related AML
3. Patients included in the BIG-1 protocol
4. Patients in first CR or CRp/CRi following 1 or 2 courses of induction chemotherapy
according to BIG-1 protocol and who are planned to receive consolidation.
5. Patients stratified within the favorable and intermediate risk groups as defined by
BIG-1 protocol
6. ECOG performance status ≤ 2
7. Left ventricular ejection fraction (LVEF) at least 40% by multiple gated acquisition
(MUGA) scan or echocardiogram (ECHO)
8. Creatinine clearance ≥ 30 ml/min (calculated by the usual method of each
institution), total bilirubin ≤ 1.5 times the ULN; ASAT and ALAT ≤ times the upper
limit of normal (ULN)
9. Absence of uncontrolled infection
10. Women of childbearing potential must agree to use effective contraception without
interruption throughout the study and for a further 3 months after the end of
treatment
11. Written signed informed consent
Exclusion criteria
1.AML stratified in the unfavorable BIG-1 risk-group. 2.Diagnosis of Acute Promyelocytic
Leukemia or CBF AML (ie. AML with t(8;21), t(16,16) or inv(16), or their molecular
equivalents RUNX1-RUNX1T1 and CBFB-MYH11) 3.AML secondary to prior myeloproliferative
disorder according to WHO classification (2008) and Philadelphia chromosome-positive AML
(Ph1+) 4.Absence of CR/CRp/CRi after a maximum of two chemotherapy cycles 5.Severe
medical or mental condition precluding the administration of protocol treatments 6.Prior
history of cancer unless controlled for at least 2 years and except for basocellular
cutaneous cancers and in situ cervix cancers 7.Positive pregnancy test 8.Breast feeding
9.Uncontrolled infection such as sepsis, or multiple organ dysfunction syndrome,
uncontrolled fever 10.Documented uncontrolled fungal infection (positive blood test and
cultures) 11.Prior venetoclax exposure 12.Known HBV with detectable viral load 13.Known
HIV positive patients 14.Known hypersensitivity to any of the study medication 15.History
of myocardial infarction, unstable angina, cerebrovascular accident (CVA) or transient
ischemic attack (TIA) in the 3 months before randomization 16.Patient under hemodialysis
(HD) or peritoneal dialysis (PD) 17.Concomitant treatment with cytochrome CYP3A4
inhibitor which cannot be stopped during venetoclax administration ONLY FOR PHASE 1
18.During the phase 2, for patients randomized in the IDAC + Venetoclax arm, if
concomitant treatment with cytochrome CYP3A4 inhibitor cannot be stopped, a dose
reduction of 70% of venetoclax must be apply
For randomization R3 (before AlloHSCT):
Inclusion criteria
1. Patients enrolled in the BIG-1 trial at diagnosis
2. Patient presenting with AML in first CR or CRp/CRi treated in the BIG-1 trial and
classified in the intermediate risk group, namely:
- either initially favorable but poor molecular responders for NPM1 MRD: NPM1
mutation, without FLT3-ITD mutation or with an FLT3-ITD ratio < 0.50 and MRD2
positive blood (decrease of less than 4 log from baseline at diagnosis)).
- Or initially favorable but requiring two cycles of chemotherapy (a salvage
therapy) to obtain the first CR/CRp/CRi
- Or other immediate intermediaries
3. No metastatic or progressive cancer, with the exception of basal cell skin carcinoma
and cervical carcinoma in situ
4. Patients with general condition preserved (ECOG ≤ 3) and with no uncontrolled severe
infection
5. Women of childbearing age must make use of effective contraception
6. Patients who are covered by or beneficiaries of a social security system (Social
Security or Universal Medical Coverage).
7. Patients who have read and understood the information sheet and signed the informed
consent form
Exclusion criteria
1. Complete remission is not obtained (CR, CRp/CRi) after induction and/or salvage
therapy
2. Patient presenting with AML in first CR or CRp/CRi treated in the BIG-1 trial and
classified either in the favorable risk group or the unfavorable risk group
3. Patients with a severe organ or psychiatric pathology, presumed to be independent of
AML and contraindicating the allograft
4. Patients who, for family, social or geographic reasons, do not wish to be regularly
monitored via consultation
5. Uncontrolled severe infection at the time of inclusion
6. Serology positive for HIV 1 or 2 or HTLV 1 or 2, or active HBV or HCV viral
infection
7. Pregnant women (beta-HCG positive) or currently breastfeeding
8. Adult patient who is incapacitated, under wardship, legal guardianship, or under the
protection of the courts
9. Patients under State Medical Assistance (AME)
1. Age ≥ 18 years and < 61 years
2. With a newly diagnosed de novo or secondary type AML (post myelodysplastic syndrome
MDS or therapy-related AML)
3. No prior treatment for neither AML (with the exception of hydroxyurea), nor MDS
(with the exception of EPO)
4. ECOG performance status ≤ 3
5. Absence of severe uncontrolled infection
6. 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%
7. 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
8. Genetic mutation testing of the FLT3 (FLT3-ITD ou FLT3-TKD) gene, performed in local
or central laboratory
9. 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
10. Patients who are covered by or beneficiaries of a social security system (Social
Security or Universal Medical Coverage)
11. Patients who have read and understood the information sheet and signed the informed
consent form
Exclusion criteria (at diagnosis) :
1.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).
3.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) :
Inclusion criteria
1. Patients enrolled in the BIG-1 trial at diagnosis
2. 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)
3. Favorable or intermediate risk AML patients, as stratified with BIG-1 prognostic
classification
4. Patients randomized to R2-IDAC arm (intermediate dose cytarabine)
5. ECOG performance status ≤ 2
6. Left ventricular ejection fraction (LVEF) at least 40% by multiple gated acquisition
(MUGA) scan or echocardiogram (ECHO)
7. 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
8. Signed written informed consent for vosaroxin study (R4-VOS)
9. Women of childbearing potential must have a negative pregnancy test within 8 days
before randomization R4-VOS and commit to the use of effective contraception during
the period of treatment and up to 36 days after vosaroxin has been stopped. Men must
use effective contraception during the treatment period and up to 96 days after
vosaroxin has been stopped.
Exclusion criteria
1.Patients classified in the unfavorable risk group according to the BIG-1 protocol
classification 2.Complete remission is not attained (CR, CRp/CRi) after induction and/or
salvage therapy 3.Positive pregnancy test 4.Severe uncontrolled infection such as sepsis,
or multiple organ dysfunction syndrome, uncontrolled fever 5.Documented uncontrolled
fungal infection (positive blood test and cultures) 6.History of myocardial infarction,
unstable angina, cerebrovascular accident (CVA) or transient ischemic attack (TIA) in the
3 months before randomization 7.Patient under hemodialysis (HD) or peritoneal dialysis
(PD)
For randomization R4-DEX (post-induction/salvage) :
Inclusion criteria
1. Patients enrolled in the BIG-1 trial at diagnosis
2. 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-DEX)
3. Favorable or intermediate risk AML patients, as stratified with BIG-1 prognostic
classification
4. ECOG performance status ≤ 2
5. Local clinical laboratory values as follows:
- Serum creatinine ≤ 150 µmol/L
- 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
6. Signed written informed consent for dexamethasone study (R4-DEX)
Exclusion criteria
1.Severe uncontrolled infection such as sepsis, or multiple organ dysfunction syndrome,
uncontrolled fever 2.Documented uncontrolled fungal infection (positive blood test and
cultures 3.History of myocardial infarction, unstable angina, cerebrovascular accident
(CVA) or transient ischemic attack (TIA) in the 3 months before randomization 4.Patient
under hemodialysis (HD) or peritoneal dialysis (PD)
For randomization R4-VEN (post-induction/salvage) :
Inclusion criteria
1. Age 18 - 60 years at inclusion in BIG-1 protocol
2. diagnosis of AML according to WHO classification de novo or secondary to
myelodysplastic syndrome (myelodysplastic syndrome must not have been treated except
by ESA, Lenalidomide or non-chemotherapy) or therapy-related AML
3. Patients included in the BIG-1 protocol
4. Patients in first CR or CRp/CRi following 1 or 2 courses of induction chemotherapy
according to BIG-1 protocol and who are planned to receive consolidation.
5. Patients stratified within the favorable and intermediate risk groups as defined by
BIG-1 protocol
6. ECOG performance status ≤ 2
7. Left ventricular ejection fraction (LVEF) at least 40% by multiple gated acquisition
(MUGA) scan or echocardiogram (ECHO)
8. Creatinine clearance ≥ 30 ml/min (calculated by the usual method of each
institution), total bilirubin ≤ 1.5 times the ULN; ASAT and ALAT ≤ times the upper
limit of normal (ULN)
9. Absence of uncontrolled infection
10. Women of childbearing potential must agree to use effective contraception without
interruption throughout the study and for a further 3 months after the end of
treatment
11. Written signed informed consent
Exclusion criteria
1.AML stratified in the unfavorable BIG-1 risk-group. 2.Diagnosis of Acute Promyelocytic
Leukemia or CBF AML (ie. AML with t(8;21), t(16,16) or inv(16), or their molecular
equivalents RUNX1-RUNX1T1 and CBFB-MYH11) 3.AML secondary to prior myeloproliferative
disorder according to WHO classification (2008) and Philadelphia chromosome-positive AML
(Ph1+) 4.Absence of CR/CRp/CRi after a maximum of two chemotherapy cycles 5.Severe
medical or mental condition precluding the administration of protocol treatments 6.Prior
history of cancer unless controlled for at least 2 years and except for basocellular
cutaneous cancers and in situ cervix cancers 7.Positive pregnancy test 8.Breast feeding
9.Uncontrolled infection such as sepsis, or multiple organ dysfunction syndrome,
uncontrolled fever 10.Documented uncontrolled fungal infection (positive blood test and
cultures) 11.Prior venetoclax exposure 12.Known HBV with detectable viral load 13.Known
HIV positive patients 14.Known hypersensitivity to any of the study medication 15.History
of myocardial infarction, unstable angina, cerebrovascular accident (CVA) or transient
ischemic attack (TIA) in the 3 months before randomization 16.Patient under hemodialysis
(HD) or peritoneal dialysis (PD) 17.Concomitant treatment with cytochrome CYP3A4
inhibitor which cannot be stopped during venetoclax administration ONLY FOR PHASE 1
18.During the phase 2, for patients randomized in the IDAC + Venetoclax arm, if
concomitant treatment with cytochrome CYP3A4 inhibitor cannot be stopped, a dose
reduction of 70% of venetoclax must be apply
For randomization R3 (before AlloHSCT):
Inclusion criteria
1. Patients enrolled in the BIG-1 trial at diagnosis
2. Patient presenting with AML in first CR or CRp/CRi treated in the BIG-1 trial and
classified in the intermediate risk group, namely:
- either initially favorable but poor molecular responders for NPM1 MRD: NPM1
mutation, without FLT3-ITD mutation or with an FLT3-ITD ratio < 0.50 and MRD2
positive blood (decrease of less than 4 log from baseline at diagnosis)).
- Or initially favorable but requiring two cycles of chemotherapy (a salvage
therapy) to obtain the first CR/CRp/CRi
- Or other immediate intermediaries
3. No metastatic or progressive cancer, with the exception of basal cell skin carcinoma
and cervical carcinoma in situ
4. Patients with general condition preserved (ECOG ≤ 3) and with no uncontrolled severe
infection
5. Women of childbearing age must make use of effective contraception
6. Patients who are covered by or beneficiaries of a social security system (Social
Security or Universal Medical Coverage).
7. Patients who have read and understood the information sheet and signed the informed
consent form
Exclusion criteria
1. Complete remission is not obtained (CR, CRp/CRi) after induction and/or salvage
therapy
2. Patient presenting with AML in first CR or CRp/CRi treated in the BIG-1 trial and
classified either in the favorable risk group or the unfavorable risk group
3. Patients with a severe organ or psychiatric pathology, presumed to be independent of
AML and contraindicating the allograft
4. Patients who, for family, social or geographic reasons, do not wish to be regularly
monitored via consultation
5. Uncontrolled severe infection at the time of inclusion
6. Serology positive for HIV 1 or 2 or HTLV 1 or 2, or active HBV or HCV viral
infection
7. Pregnant women (beta-HCG positive) or currently breastfeeding
8. Adult patient who is incapacitated, under wardship, legal guardianship, or under the
protection of the courts
9. Patients under State Medical Assistance (AME)