Combination of BTK Inhibitor Overcomes Drug-resistance in Refractory/Relapsed FLT3 Mutant AML

Study Overview
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Brief Summary
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Clinical efficacy of FLT3 inhibitors combining with chemotherapy is usually transient and followed by emergence of drug-resistance in FLT3-ITD mutant AML. BTK is reported to be a therapeutic target in this subtype leukemia. Our previous study showed inhibition of BTK onvercome drug-resistance to FLT3 inhibitors/chemotherapy in refractory/relapsed FLT3 mutant AML. In this prospective randomized controlled study, the efficacy and safety of combination of BTK inhibitor with chemotherapy with/without FLT3 inhibitor in refractory/relapsed FLT3 mutant AML are evaluated.

Detailed Description
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Clinical efficacy of FLT3 inhibitors combining with chemotherapy is usually transient and followed by emergence of drug-resistance in FLT3-ITD mutant acute myeloid leukemia (AML). How to overcome the resistance to FLT3 inhibitors or chemotherapy needs further study. Bruton's tyrosine kinase (BTK) is reported to be a therapeutic target in this subtype leukemia. Our previous study showed inhibition of BTK onvercome drug-resistance to FLT3 inhibitors/chemotherapy in refractory/relapsed FLT3 mutant AML. In this prospective randomized controlled study, we are going to inhibit BTK with BTK inhibitor ibrutinib in the patients with refractory/relapsed FLT3 mutant AML, and then test the enhancing effect and safety of combination of ibrutinib with chemotherapy with/without FLT3 inhibitor, to make sure inhibition of BTK overcomes drug-resistance in FLT3 mutation AML.

Official Title
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Combination of Brutons Tyrosine Kinase (BTK) Inhibitor Overcomes Drug-resistance in Refractory/Relapsed FLT3 Mutant Acute Myeloid Leukemia (AML)

Conditions
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FLT3-ITD Mutation, Acute Myeloid Leukemia, Brutons Tyrosine Kinase

Intervention / Treatment
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* Drug: Ibrutinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Refractoty/relapsed FLT3-ITD mutation AML Age 14-60 Exclusion Criteria: Any abnormality in a vital sign (e.g., heart rate, respiratory rate, or blood pressure) Patients with any conditions not suitable for the trial (investigators' decision)

Ages Eligible for Study
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Minimum Age: 14 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 |
| --- | --- |
| Experimental: BTK treatment<br>Ibrutinib 420mg day -3 to d14; Decitabine 20mg/m2 d1-5; Aclacinomycin 10mg/m2 d1-5; Cytarabine 15mg/m2 q12h d1-14; G-CSF 200ug/m2 -12h to d14; Sorafenib 0.4g bid continously at the condition of being naive to sorafenib. | Drug: Ibrutinib<br>* Ibrutinib 420mg day -3 to d14 combining with chemotherapy with/without sorafenib based on whether the patients are naive to sorafenib before relapse.<br>|
| Active Comparator: BTK-free treatment<br>Decitabine 20mg/m2 d1-5; Aclacinomycin 10mg/m2 d1-5; Cytarabine 15mg/m2 q12h d1-14; G-CSF 200ug/m2 -12h to d14; Sorafenib 0.4g bid continously at the condition of being naive to sorafenib. | Drug: Ibrutinib<br>* Ibrutinib 420mg day -3 to d14 combining with chemotherapy with/without sorafenib based on whether the patients are naive to sorafenib before relapse.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| CR rate |  | After the first and second cycle induction | 
| OS |  | 2 years | 
| DFS |  | 2 years |