Acute Myeloid Leukemia (AML)
Conditions
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.
Interventions
DRUGIdarubicin
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).
DRUGDaunorubicin
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).
DRUGHD Cytarabine
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
DRUGCyclosporine
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
DRUGMethotrexate
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
DRUGvosaroxin
Consolidation chemotherapy course (s) : -70 mg/m² on D1 and D4
DRUGID cytarabine
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
DRUGDexamethasone
Consolidation chemotherapy course (s) : -10 mg/12h on D1, D3 and D5
DRUGVenetoclax
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)
Sponsors
University Hospital, Angers
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 61 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall survival | 3 years | For randomizations R1 (idarubicine vs daunorubicine) and R2 (HDAC vs IDAC) |
| Cumulative incidence (CI) of acute Graft versus Host Disease (GvHD) of grade II to IV | 100 days | For randomization R3 : GvHD prophylaxis study |
| Disease free survival | 18 months | For randomizations R4 |
Countries
France
Contacts
Primary ContactMathilde Hunault, PD
Backup ContactDRCI Promotion Interne
Outcome results
None listed