Timed-Sequential Induction in CBF-AML

December 19, 2013 updated by: Assistance Publique - Hôpitaux de Paris

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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)

Study Type

Interventional

Enrollment (Actual)

200

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • France
      • Nimes, France, 30029
        • Service Hematologie Oncologie

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

16 years to 58 years (Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
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)
Drug: Chemotherapy (DAUNORUBICINE-CYTARABINE)
Chemotherapy induction sequential
Other Names:
  • Chemotherapy induction SEQUENTIAL
Experimental: 1
BRAS INDUCTION SEQUENTIAL
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)
Drug: Chemotherapy (DAUNORUBICINE-CYTARABINE)
Chemotherapy induction sequential
Other Names:
  • Chemotherapy induction SEQUENTIAL

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
The primary objective of the study is to increase the Event-free Survival (EFS)
Time Frame: during the 60 months
during the 60 months

Secondary Outcome Measures

Outcome Measure
Time Frame
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
during the 60 months
The toxicity of both induction strategies (induction deaths and further deaths in first CR).
Time Frame: during the 60 months
during the 60 months
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
during the 60 months
The prognostic value of CBF-AML subsets defined on Gene Expression Profiling (GEP) basis.
Time Frame: during the 60 months
during the 60 months
The prognostic impact of known polymorphisms of genes involved in the metabolism of cytarabine and anthracyclines (Pharmacogenetic study).
Time Frame: during the 60 months
during the 60 months
of patients with CBF-AML through the administration of a systematic
Time Frame: during the 60 months
during the 60 months
timed-sequential induction (arm A) as compared to a response-adapted
Time Frame: during the 60 months
during the 60 months
timed-sequential induction (arm G).
Time Frame: during the 60 months
during the 60 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Assistance Publique - Hôpitaux de Paris

Collaborators

French Innovative Leukemia Organisation
Acute Leukemia French Association

Investigators

  • Principal Investigator: Eric JOURDAN, MD,PhD, Assistance Publique - Hôpitaux de Paris

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

July 1, 2007

Primary Completion (Actual)

June 1, 2011

Study Completion (Actual)

June 1, 2011

Study Registration Dates

First Submitted

January 29, 2007

First Submitted That Met QC Criteria

January 29, 2007

First Posted (Estimate)

January 30, 2007

Study Record Updates

Last Update Posted (Estimate)

December 20, 2013

Last Update Submitted That Met QC Criteria

December 19, 2013

Last Verified

July 1, 2007

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • P060504

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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