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Timed-Sequential Induction in CBF-AML

This study has been completed.
Sponsor:
Collaborators:
Acute Leukemia French Association
Groupe Ouest Est d'Etude des Leucémies et Autres Maladies du Sang GOELAMS
Information provided by (Responsible Party):
Assistance Publique - Hôpitaux de Paris
ClinicalTrials.gov Identifier:
NCT00428558
First received: January 29, 2007
Last updated: December 19, 2013
Last verified: July 2007

January 29, 2007
December 19, 2013
July 2007
June 2011   (final data collection date for primary outcome measure)
The primary objective of the study is to increase the Event-free Survival (EFS) [ Time Frame: during the 60 months ] [ Designated as safety issue: No ]
  • The primary objective of the study is to increase the Event-free Survival (EFS)
  • of patients with CBF-AML through the administration of a systematic
  • timed-sequential induction (arm A) as compared to a response-adapted
  • timed-sequential induction (arm G).
Complete list of historical versions of study NCT00428558 on ClinicalTrials.gov Archive Site
  • The complete remission (CR) rate, molecular response (MRD), cumulative incidence of relapse (CIR), disease-free survival (DFS), and overall survival (OS) in both randomization groups. [ Time Frame: during the 60 months ] [ Designated as safety issue: Yes ]
  • The toxicity of both induction strategies (induction deaths and further deaths in first CR). [ Time Frame: during the 60 months ] [ Designated as safety issue: Yes ]
  • The relative prognostic value of : 1) WBC; 2) Mutational status (FLT3, c-Kit, and Ras mutations); and 3) MRD in patient outcome (CR rate, CIR, EFS, DFS, OS). [ Time Frame: during the 60 months ] [ Designated as safety issue: Yes ]
  • The prognostic value of CBF-AML subsets defined on Gene Expression Profiling (GEP) basis. [ Time Frame: during the 60 months ] [ Designated as safety issue: No ]
  • The prognostic impact of known polymorphisms of genes involved in the metabolism of cytarabine and anthracyclines (Pharmacogenetic study). [ Time Frame: during the 60 months ] [ Designated as safety issue: Yes ]
  • of patients with CBF-AML through the administration of a systematic [ Time Frame: during the 60 months ] [ Designated as safety issue: No ]
  • timed-sequential induction (arm A) as compared to a response-adapted [ Time Frame: during the 60 months ] [ Designated as safety issue: No ]
  • timed-sequential induction (arm G). [ Time Frame: during the 60 months ] [ Designated as safety issue: No ]
  • The complete remission (CR) rate, molecular response (MRD), cumulative incidence of relapse (CIR), disease-free survival (DFS), and overall survival (OS) in both randomization groups.
  • The toxicity of both induction strategies (induction deaths and further deaths in first CR).
  • The relative prognostic value of : 1) WBC; 2) Mutational status (FLT3, c-Kit, and Ras mutations); and 3) MRD in patient outcome (CR rate, CIR, EFS, DFS, OS).
  • The prognostic value of CBF-AML subsets defined on Gene Expression Profiling (GEP) basis.
  • The prognostic impact of known polymorphisms of genes involved in the metabolism of cytarabine and anthracyclines (Pharmacogenetic study).
Not Provided
Not Provided
 
Timed-Sequential Induction in CBF-AML
A Phase 3 Trial of Systematic Versus Response-adapted Timed-Sequential Induction in Patients With Core Binding Factor (CBF) Acute Myeloid Leukemia (AML)

Core binding factor (CBF) acute myeloid leukemias (AML) include AMLs carrying the t(8;21) translocation as well as AMLs carrying either the inversion of chromosome 16 or translocation t(16;16). CBF-AMLs are characterized by their high sensitivity to standard chemotherapeutical agents, especially to cytarabine when administered as high-dose bolus infusions, and thus by a relative good prognosis. However, relapse rates are still comprised between 30 and 50% in these patients, even if overall survival may reach approximately 65% due to the potential salvage of late relapses.

The primary purpose of the protocol is to compare two modalities of timed-sequential induction in order to improve the results of the treatment of CBF-AML patients. This protocol also includes the biological characterization of the heterogeneity of these diseases (gene mutation and transcription profiles), as well as a centralized minimal residual disease monitoring and centralized evaluation of pharmacogenetic polymorphisms.

Core binding factor (CBF) acute myeloid leukemias (AML) include AMLs carrying the t(8;21) translocation as well as AMLs carrying either the inversion of chromosome 16 or translocation t(16;16). CBF-AMLs are characterized by their high sensitivity to standard chemotherapeutical agents, especially to cytarabine when administered as high-dose bolus infusions, and thus by a relative good prognosis. However, relapse rates are still comprised between 30 and 50% in these patients, even if overall survival may reach approximately 65% due to the potential salvage of late relapses. Initial high white blood cell count, activating mutations of cKit, Ras, and FLT3 genes, and persistence of high minimal residual disease (MRD) levels (as evidenced by AML1-ETO or CBFb-MYH11 specific RQ-PCR tools) are the main bad-prognostic factors in patients with CBF-AML.

This project includes a new single French protocol to treat patients with CBF-AML who represent approximately 15% of all AML patients. This common protocol has been elaborated by the two main French cooperative groups for adult AML (ALFA and GOELAMS). In addition to a unique specific therapeutical strategy, this protocol includes the biological characterization of the heterogeneity of these diseases (gene mutation and transcription profiles), as well as a centralized MRD monitoring and centralized evaluation of pharmacogenetic polymorphisms. This project which is well-positioned in the international competition, will use many platforms of the POLECANCER with the following objectives : 1) to improve the results of the treatment of CBF-AML patients; 2) to organize a French clinical and biological network on CBF-AML with the aim to test new targeted therapeutical agents (tyrosine kinase and/or farnesyl transferase inhibitors) in the next future.

TREATMENT DESIGN Induction course Systematic timed-sequential induction (arm A) DAUNORUBICINE (DNR): 60 mg/m2/day IV (30 min), Day 1, 2, and 3 CYTARABINE (AraC): 500 mg/m2/day Continuous infusion, Day 1 to 3 DAUNORUBICINE (DNR): 35 mg/m2/day IV (30 min), Day 8 and 9 CYTARABINE (AraC): 1 gr/m2/12 h IV (2h), Day 8, 9, and 10 Response-adapted timed-sequential induction (arm G) DAUNORUBICINE (DNR): 60 mg/m2/dayIV (30 min), Day 1, 2, and 3 CYTARABINE (AraC): 200 mg/m2/dayContinuous infusion, Day 1 to 7

Peripheral blood and bone marrow evaluation at Day 15. The following second induction course will be administered in patients with persistent marrow disease at Day 15 :

DAUNORUBICINE (DNR): 35 mg/m2/day IV (30 min), Day 16 and 17 CYTARABINE (AraC)1 gr/m2/12 h IV (2h), Day 16, 17, and 18 Persistent marrow disease at Day 15 is defined by more than 10% leukemic blasts in a non aplastic or non very hypoplastic bone marrow aspiration sample.

Salvage course In patients not reaching CR after the first induction course (either SI or TSI), a salvage course will be administered. Salvage therapy should not be initiated before Day 35 of arm A and Day 42 of arm G.

CYTARABINE (AraC) :3 gr/m2/12h IV (2h), Day 1, 3, 5, and 7 AMSACRINE : 100 mg/m2/day IV (30 min), Day 5 to 7 G-CSF lenograstim : from Day 8 until myeloid recovery (> 500 PMN/µL)

Consolidation cycles Three monthly cycles of consolidation will be administered in all patients reaching hematological CR after induction or induction + salvage.

CYTARABINE (AraC): 3 g/m2/12h IV (2h), Day 1, 3, and 5 G-CSF lenograstim : from Day 8 until myeloid recovery (> 500 PMN/µL)

Interventional
Phase 3
Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Acute Myeloid Leukemia
  • Drug: Chemotherapy (DAUNORUBICINE-CYTARABINE)
    A Phase 3 Trial of Systematic versus Response-adapted Timed-SEQUENTIAL Induction in Patients with Core Binding Factor (CBF) Acute Myeloid Leukemia (AML)
    Other Name: Chemotherapy (DAUNORUBICINE-CYTARABINE)
  • Drug: Chemotherapy (DAUNORUBICINE-CYTARABINE)
    Chemotherapy induction sequential
    Other Name: Chemotherapy induction SEQUENTIAL
  • Active Comparator: 2
    A Phase 3 Trial of Systematic versus Response-adapted Timed-SEQUENTIAL Induction in Patients with Core Binding Factor (CBF) Acute Myeloid Leukemia (AML)
    Intervention: Drug: Chemotherapy (DAUNORUBICINE-CYTARABINE)
  • Experimental: 1
    BRAS INDUCTION SEQUENTIAL
    Intervention: Drug: Chemotherapy (DAUNORUBICINE-CYTARABINE)

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
200
June 2011
June 2011   (final data collection date for primary outcome measure)

Inclusion Criteria:

  • Patients aged 18-60 years.
  • With a newly-diagnosed de novo or therapy-related CBF-AML defined

Exclusion Criteria:

  • No previously treated with any anti-leukemic agent.
  • No presenting any diagnosis of uncontrolled or metastatic tumor.
  • OMS performance status < 2,
  • Absence of uncontrolled severe infection,
  • AST and ALT 2.5 x ULN,
  • Total bilirubin 1.5 x ULN,
  • Serum creatinine 1.5 x ULN
Both
18 Years to 60 Years
No
Contact information is only displayed when the study is recruiting subjects
France
 
NCT00428558
P060504
No
Assistance Publique - Hôpitaux de Paris
Assistance Publique - Hôpitaux de Paris
  • Acute Leukemia French Association
  • Groupe Ouest Est d'Etude des Leucémies et Autres Maladies du Sang GOELAMS
Principal Investigator: Eric JOURDAN, MD,PhD Assistance Publique - Hôpitaux de Paris
Assistance Publique - Hôpitaux de Paris
July 2007

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