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
  Purpose

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.


Condition Intervention Phase
Acute Myeloid Leukemia
Drug: Chemotherapy (DAUNORUBICINE-CYTARABINE)
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase 3 Trial of Systematic Versus Response-adapted Timed-Sequential Induction in Patients With Core Binding Factor (CBF) Acute Myeloid Leukemia (AML)

Resource links provided by NLM:


Further study details as provided by Assistance Publique - Hôpitaux de Paris:

Primary Outcome Measures:
  • 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 ]

Secondary Outcome Measures:
  • 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 ]

Enrollment: 200
Study Start Date: July 2007
Study Completion Date: June 2011
Primary Completion Date: June 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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)
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)
Experimental: 1
BRAS INDUCTION SEQUENTIAL
Drug: Chemotherapy (DAUNORUBICINE-CYTARABINE)
Chemotherapy induction sequential
Other Name: Chemotherapy induction SEQUENTIAL

Detailed Description:

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)

  Eligibility

Ages Eligible for Study:   18 Years to 60 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
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, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00428558

Locations
France
Service Hematologie Oncologie
Nimes, France, 30029
Sponsors and Collaborators
Assistance Publique - Hôpitaux de Paris
Acute Leukemia French Association
Groupe Ouest Est d'Etude des Leucémies et Autres Maladies du Sang GOELAMS
Investigators
Principal Investigator: Eric JOURDAN, MD,PhD Assistance Publique - Hôpitaux de Paris
  More Information

Publications:
Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Assistance Publique - Hôpitaux de Paris
ClinicalTrials.gov Identifier: NCT00428558     History of Changes
Other Study ID Numbers: P060504
Study First Received: January 29, 2007
Last Updated: December 19, 2013
Health Authority: France: Ministry of Health

Keywords provided by Assistance Publique - Hôpitaux de Paris:
acute myeloid leukemia
Core Binding Factor
t(8;21)
inv(16)
timed-sequential induction

Additional relevant MeSH terms:
Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Neoplasms
Neoplasms by Histologic Type
Cytarabine
Anti-Infective Agents
Antimetabolites
Antimetabolites, Antineoplastic
Antineoplastic Agents
Antiviral Agents
Immunologic Factors
Immunosuppressive Agents
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Physiological Effects of Drugs
Therapeutic Uses

ClinicalTrials.gov processed this record on October 20, 2014