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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)

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ClinicalTrials.gov Identifier: NCT02416388
Recruitment Status : Recruiting
First Posted : April 15, 2015
Last Update Posted : April 14, 2017
Sponsor:
Information provided by (Responsible Party):
University Hospital, Angers

Tracking Information
First Submitted Date  ICMJE April 7, 2015
First Posted Date  ICMJE April 15, 2015
Last Update Posted Date April 14, 2017
Study Start Date  ICMJE January 2015
Estimated Primary Completion Date June 2024   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 12, 2017)
  • Overall survival [ Time Frame: 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 [ Time Frame: 100 days ]
    For randomization R3 : GvHD prophylaxis study
  • Disease free survival [ Time Frame: 18 months ]
    For randomizations R4
Original Primary Outcome Measures  ICMJE
 (submitted: April 9, 2015)
  • Overall survival [ Time Frame: 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 [ Time Frame: 100 days ]
    For randomization R3 : GvHD prophylaxis study
  • Disease free survival [ Time Frame: 18 months ]
    For randomization R4 (if new molecules are to be added to the study backbone)
Change History Complete list of historical versions of study NCT02416388 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE Not Provided
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE 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
Official Title  ICMJE 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
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.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Acute Myeloid Leukemia (AML)
Intervention  ICMJE
  • Drug: Idarubicin

    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).

  • Drug: Daunorubicin

    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).

  • Drug: HD 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

  • Drug: Cyclosporine

    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

  • Drug: Methotrexate

    GvHD prophylaxis post allogeneic SCT :

    -15 mg/m² on D+1 then 10 mg/m² on D+3, D+6 and D+11

  • Drug: Mycophenolic acid (MPA)

    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
  • Drug: vosaroxin

    Consolidation chemotherapy course (s) :

    -70 mg/m² on D1 and D4

  • Drug: ID 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

Study Arms  ICMJE
  • Experimental: R1-IDA
    Idarubicin
    Intervention: Drug: Idarubicin
  • Active Comparator: R1-DAUNO
    Daunorubicin
    Intervention: Drug: Daunorubicin
  • Active Comparator: R2-HDAC
    High dose cytarabine
    Intervention: Drug: HD Cytarabine
  • Experimental: R2-IDAC
    Intermediate dose cytarabine
    Intervention: Drug: ID cytarabine
  • Active Comparator: R3-MAC-MTX
    Methotrexate and mycophenolic acid
    Interventions:
    • Drug: Methotrexate
    • Drug: Mycophenolic acid (MPA)
  • Experimental: R3-MAC-MPA
    Cyclosporine and mycophenolic acid
    Interventions:
    • Drug: Cyclosporine
    • Drug: Mycophenolic acid (MPA)
  • Active Comparator: R3-RIC-CICLO
    Cyclosporine
    Intervention: Drug: Cyclosporine
  • Experimental: R3-RIC-MPA
    Cyclosporine and mycophenolic acid
    Interventions:
    • Drug: Cyclosporine
    • Drug: Mycophenolic acid (MPA)
  • Experimental: R4-VOS-IDAC
    Intermediate dose cytarabine and vosaroxin
    Interventions:
    • Drug: vosaroxin
    • Drug: ID cytarabine
  • Active Comparator: R4-IDAC
    Intermediate dose cytarabine
    Intervention: Drug: ID cytarabine
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: April 9, 2015)
3100
Original Estimated Enrollment  ICMJE Same as current
Study Completion Date  ICMJE Not Provided
Estimated Primary Completion Date June 2024   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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 AML, with the exception of hydroxyurea
  4. ECOG performance status ≤ 3
  5. No contraindication to anthracyclines : decompensated or uncontrolled heart failure, recent myocardial infarction, current signs of cardiac impairment, uncontrolled arrhythmias, LVEF (left ventricular ejection fraction) < 50%
  6. 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
  7. Women of childbearing potential should use appropriate methods of contraception
  8. Health insurance coverage
  9. Signed informed consent

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 pshyciatric 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. Patients achieving first CR/CRp/CRi after induction or salvage therapy (within 15 days before 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:

    • Serum creatinine ≤ 2.0 mg/dL
    • 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. 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 R3 (before AlloHSCT):

Inclusion criteria

  1. Patients enrolled in the BIG-1 trial at diagnosis
  2. Patients achieving first CR after induction or salvage therapy
  3. Patients belonging to the intermediate AML risk group as defined in the protocol BIG-1
  4. Signed informed consent for R3
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 61 Years   (Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Mathilde Hunault, PD MaHunault@chu-angers.fr
Contact: Annabelle Boussault + 33 241 356 490 annabelle.boussaul@chu-angers.fr
Listed Location Countries  ICMJE France
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02416388
Other Study ID Numbers  ICMJE PHRC-2010-03
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party University Hospital, Angers
Study Sponsor  ICMJE University Hospital, Angers
Collaborators  ICMJE Not Provided
Investigators  ICMJE Not Provided
PRS Account University Hospital, Angers
Verification Date April 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP