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

• Register: ClinicalTrials.gov
• Last refreshed on: 12 December 2020
• Main ID: NCT02416388
• Date of registration: 07/04/2015
• Prospective Registration: No
• Primary sponsor: University Hospital, Angers
• Public title: 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
• Scientific title: 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
• Date of first enrolment: January 2015
• Target sample size: 3100
• Recruitment status: Recruiting
• URL: https://clinicaltrials.gov/show/NCT02416388
• Study type: Interventional
• Study design: Allocation: Randomized. Intervention model: Parallel Assignment. Primary purpose: Treatment. Masking: None (Open Label).
• Phase: Phase 2/Phase 3

Countries of recruitment

France

Contacts

• Name: Mathilde Hunault, PD

Key inclusion & exclusion criteria

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)

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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)

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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)

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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 pro


Age minimum: 18 Years
Age maximum: 61 Years
Gender: All

Health Condition(s) or Problem(s) studied

Acute Myeloid Leukemia (AML)

Intervention(s)

Drug: Cyclosporine

Drug: Mycophenolic acid (MPA)

Drug: Venetoclax

Drug: Daunorubicin

Drug: Dexamethasone

Drug: ID cytarabine

Drug: Idarubicin

Drug: Methotrexate

Drug: vosaroxin

Drug: HD Cytarabine

Primary Outcome(s)

Cumulative incidence (CI) of acute Graft versus Host Disease (GvHD) of grade II to IV [Time Frame: 100 days]

Disease free survival [Time Frame: 18 months]

Overall survival [Time Frame: 3 years]

Secondary ID(s)

PHRC-2010-03

Source(s) of Monetary Support

Please refer to primary and secondary sponsors