Combination of Sorafenib With Standard Therapy in Newly Diagnosed Adult CBF AML

Study Overview
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Brief Summary
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Core-binding factor acute myeloid leukemia accounts for 10-15% of AML and is categorized as favorable-risk AML. However, the 5-year CIR was up to 40% in this group of patients. Emerging data show that a high frequency of mutations and/or high expression of KIT in CBF AML. Sorafenib is a multitargeted TKI, thus the purpose of this study is to evaluate the safety and efficacy of sorafenib combined with standard therapy in CBF AML.

Detailed Description
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Core-binding factor acute myeloid leukemia is characterized by t(8;21) or inv(16) and accounts for 10-15% of AML. Because of the high CR rate of nearly 90% and a 5-year OS of almost 50%, CBF-AML is categorized as favorable-risk AML. However, the 5-year cumulative incidence of relapse (CIR) was up to 40% in this group of patients after high-dose cytarabine consolidation following CR. Therefore, more effective therapeutic approaches are needed. Emerging data show that a high frequency of mutations and/or high expression of KIT in CBF AML likely result in aberrant tyrosine kinase activity, leukemia cell growth and survival, and treatment resistance. Thus, pharmacologic inhibition of KIT would lead to significant antileukemia activity if combined with an optimized chemotherapy regimen in patients with CBF AML. Recent mechanistic findings also support the potential clinical benefit of KIT inhibition in CBF AML. Sorafenib is a first-generation type-II multitargeted tyrosine kinase receptor inhibitor (TKI) that suppresses various signaling pathways associated with the development of AML, such as RTK (FLT3, c-KIT), RAS/RAF, vascular endothelial growth factor (VEGF) receptor. The purpose of this study is to evaluate the safety and efficacy of sorafenib combined with standard therapy in CBF AML.

Official Title
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Prospective Evaluation of Sorafenib Combined With Standard Therapy in Newly Diagnosed Adult Core-binding Factor Acute Myeloid Leukemia: an Open-label , Randomised Controlled, Multicenter Phase II Trial

Conditions
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Core Binding Factor Acute Myeloid Leukemia

Intervention / Treatment
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* Drug: Sorafenib
* Drug: Idarubicin
* Drug: Cytarabine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must have an unequivocal diagnosis of de novo-CBF AML, prior to start therapy, documented by rearrangement of Core Binding Factor (CBF) genes, namely RUNX1/RUNX1T1 and CBFB/MYH11. Age 18 to 65 years old with ECOG performance status 0-2. Sign informed consent form, have the ability to comply with study and follow-up procedures. Patients must have Total Bilirubin ≤ 1.5 x ULN, and AST or ALT ≤ 2.5 x ULN. Patients must have Serum Creatinine ≤ 1.5 x ULN. Women of child-bearing potential must have a negative pregnancy test before starting the protocol. Exclusion Criteria: Prior therapy for AML with the following exceptions: emergency leukapheresis emergency treatment for hyperleukocytosis with hydroxyurea for ≤ 7 days. Central nervous system involvement. Presence of any uncontrolled bacterial, viral or fungal infection. Known human immunodeficiency virus (HIV) positive. An active Hepatitis B virus (HBV) or Hepatitis C virus (HCV) infection. Patients whose disease is controlled under antiviral therapy should not be excluded. Presence of other active malignancies. QTc > 470 msec (Bazett formula) on screening ECG. Presence of significant uncontrolled or active cardiovascular disease, specifically including, but not restricted to: Myocardial infarction, unstable angina and/or congestive heart failure within 3 months prior to randomization History of clinically significant (as determined by the treating physician) atrial arrhythmia or any ventricular arrhythmia Uncontrolled hypertension Taking medications that are known to be associated with Torsades de Pointes. History of hypersensitivity to any drugs or metabolites of similar chemical classes as the study treatment. Intolerance to sorafenib, namely persistence of sorafenib-related adverse events despite supportive treatment, persistence or recurrence of adverse events after dose interruption or dose reduction of sorafenib, or both of these.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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 |
| --- | --- |
| Experimental: Sorafenib<br>Induction cycle(s): IA3+7. Patients will receive sorafenib 400 mg BID on days 8-21. Consolidation Cycle 1: IA3+3. Patients will receive sorafenib 400 mg BID on days 1-21. Consolidation Cycles 2-4: MDAC. Patients will receive sorafenib 400 mg BID on days 1-21. Maintenance therapy: Single agent sorafenib 400 mg BID for one year. | Drug: Sorafenib<br>* Induction cycle(s): 400 mg BID on days 8-21. Consolidation cycles 1-4: 400 mg BID on days 1-21. Maintenance therapy: 400 mg BID for one year.<br>Drug: Idarubicin<br>* Induction cycle(s): 12 mg/m2/day on days 1-3. Consolidation cycle 1: 8 mg/m2/day administered on days 1-3.<br>Drug: Cytarabine<br>* Induction cycle(s): 100 mg/m2 by continuous IV infusion for 24 hours on days 1-7. Consolidation cycles 1-4: 2 g/m2/12h on days 1-3.<br>|
| Active Comparator: Standard therapy<br>Induction cycle(s): IA3+7. Consolidation Cycle 1: IA3+3. Consolidation Cycles 2-4: MDAC. | Drug: Idarubicin<br>* Induction cycle(s): 12 mg/m2/day on days 1-3. Consolidation cycle 1: 8 mg/m2/day administered on days 1-3.<br>Drug: Cytarabine<br>* Induction cycle(s): 100 mg/m2 by continuous IV infusion for 24 hours on days 1-7. Consolidation cycles 1-4: 2 g/m2/12h on days 1-3.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| CMR (Complete Molecular Remission) | CMR in BM after 4 cycles of chemotherapies | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival |  | 3 year | 
| Leukemia-free survival |  | 3 year | 
| Cumulative incidence of relapse |  | 3 year | 
| Adverse effects |  | 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Core Binding Factor Acute Myeloid Leukemia, Sorafenib, CMR (Complete Molecular Remission)