Working…
ClinicalTrials.gov
ClinicalTrials.gov Menu

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)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
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

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.

Condition or disease Intervention/treatment Phase
Acute Myeloid Leukemia (AML) Drug: Idarubicin Drug: Daunorubicin Drug: HD Cytarabine Drug: Cyclosporine Drug: Methotrexate Drug: Mycophenolic acid (MPA) Drug: vosaroxin Drug: ID cytarabine Phase 2 Phase 3

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 3100 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official 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
Study Start Date : January 2015
Estimated Primary Completion Date : June 2024


Arm Intervention/treatment
Experimental: R1-IDA
Idarubicin
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).


Active Comparator: R1-DAUNO
Daunorubicin
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).


Active Comparator: R2-HDAC
High dose cytarabine
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


Experimental: R2-IDAC
Intermediate dose cytarabine
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


Active Comparator: R3-MAC-MTX
Methotrexate and mycophenolic acid
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

Experimental: R3-MAC-MPA
Cyclosporine and mycophenolic acid
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: 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

Active Comparator: R3-RIC-CICLO
Cyclosporine
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


Experimental: R3-RIC-MPA
Cyclosporine and mycophenolic acid
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: 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

Experimental: R4-VOS-IDAC
Intermediate dose cytarabine and vosaroxin
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


Active Comparator: R4-IDAC
Intermediate dose cytarabine
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





Primary Outcome Measures :
  1. Overall survival [ Time Frame: 3 years ]
    For randomizations R1 (idarubicine vs daunorubicine) and R2 (HDAC vs IDAC)

  2. 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

  3. Disease free survival [ Time Frame: 18 months ]
    For randomizations R4



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   18 Years to 61 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02416388


Contacts
Layout table for location contacts
Contact: Mathilde Hunault, PD MaHunault@chu-angers.fr
Contact: Annabelle Boussault + 33 241 356 490 annabelle.boussaul@chu-angers.fr

  Show 55 Study Locations
Sponsors and Collaborators
University Hospital, Angers

Layout table for additonal information
Responsible Party: University Hospital, Angers
ClinicalTrials.gov Identifier: NCT02416388     History of Changes
Other Study ID Numbers: PHRC-2010-03
First Posted: April 15, 2015    Key Record Dates
Last Update Posted: April 14, 2017
Last Verified: April 2017
Additional relevant MeSH terms:
Layout table for MeSH terms
Cytarabine
Daunorubicin
Leukemia, Myeloid, Acute
Leukemia, Myeloid
Leukemia
Neoplasms by Histologic Type
Neoplasms
Cyclosporine
Mycophenolic Acid
Methotrexate
Idarubicin
Cyclosporins
Abortifacient Agents, Nonsteroidal
Abortifacient Agents
Reproductive Control Agents
Physiological Effects of Drugs
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Dermatologic Agents
Enzyme Inhibitors
Folic Acid Antagonists
Immunosuppressive Agents
Immunologic Factors
Antirheumatic Agents
Nucleic Acid Synthesis Inhibitors
Antiviral Agents
Anti-Infective Agents
Antifungal Agents