Timed-Sequential Induction in CBF-AML

Study Overview
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Brief Summary
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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.

Detailed Description
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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)

Official Title
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A Phase 3 Trial of Systematic Versus Response-adapted Timed-Sequential Induction in Patients With Core Binding Factor (CBF) Acute Myeloid Leukemia (AML)

Conditions
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Acute Myeloid Leukemia

Intervention / Treatment
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* Drug: Chemotherapy (DAUNORUBICINE-CYTARABINE)
* Drug: Chemotherapy (DAUNORUBICINE-CYTARABINE)


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: 2<br>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)<br>* A Phase 3 Trial of Systematic versus Response-adapted Timed-SEQUENTIAL Induction in Patients with Core Binding Factor (CBF) Acute Myeloid Leukemia (AML)<br>|
| Experimental: 1<br>BRAS INDUCTION SEQUENTIAL | Drug: Chemotherapy (DAUNORUBICINE-CYTARABINE)<br>* Chemotherapy induction sequential<br>* Other names: Chemotherapy induction SEQUENTIAL;|

What is the study measuring?
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Primary Outcome Measures

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

Secondary Outcome Measures

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

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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acute myeloid leukemia, Core Binding Factor, t(8;21), inv(16), timed-sequential induction