A Clinical Trial to Evaluate Clifutinib in Patients With Relapsed or Refractory Acute Myeloid Leukemia(AML)

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of Clifutinib Besylate in Relapsed/refractory AML patients with FLT3-ITD mutation.

Detailed Description
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It is a multi-center , open-label, single arm study conducted in 2 parts. Dose-escalation part: Subjects will receive oral Clifutinib Besylate once on C0D1.After 3 days,they will receive Clifutinib Besylate once daily repeatedly until disease progression or unacceptable toxicity occurs, each cycle is defined as 28 days. Expansion part:Expansion cohort might be set to further investigate the safety and efficacy of Clifutinib Besylate at or lower MTD dose recommended by dose-escalation part.

Official Title
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A Phase I, Multi-center, Open,Single Arm, Dose-escalation Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Efficacy of Clifutinib Besylate(HEC73543) in Relapsed or Refractory Acute Myeloid Leukemia (AML)

Conditions
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Acute Myeloid Leukemia

Intervention / Treatment
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* Drug: Clifutinib Besylate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Documented acute myeloid leukemia according to World Health Organization（WHO） criteria(excluding acute promyelocytic leukemia), with FLT3-ITD gene mutation,refractory after common or enhanced chemotherapy or relapse. ECOG performance status of 0-1. Subjects must have adequate organ function and meeting all of the following laboratory review before enrollment： Lood routine examination: WBC≤2000/mm3; Liver function: Alanine aminotransferase (ALT) and Aspartate transaminase (AST) ≤2.5×upper limit of normal(ULN); serum bilirubin ≤ 1.5 × ULN; Renal function: Serum creatinine ≤ 1.5×ULN, or the creatinine clearance (CrCl)≥ 60 mL / min calculated by the Cockcroft-Gault formula; Electrolyte: serum potassium≥3.0mmol/L; serum calcium≥2.0 mmol/L;serum magnesium≥0.5 mmol/L; Coagulation function:fibrinogen≥1.0g/L; activated partial thromboplastin time( APTT)≦ULN+10s; prothrombin time(PT)≤ULN+3s. Exclusion Criteria: Received FLT3 inhibitors within 4 weeks prior to the administration; Received hematopoietic stem cell transplantation within2 months prior to the administration or received immunosuppressor beceause of GVHD; Chemotherapy, immunotherapy, radiotherapy, or major surgery within 4 weeks prior to administration; Nitrosourea and mitomycin chemotherapy within 6 weeks prior to the administration; Have taken live vaccines within 4 weeks prior to /or concurrent with the administration; Have received a trial investigational product, or participated in other clinical trials within 4 weeks prior to administration; Documented promyelocytic leukemia (t (15; 17) (q22; q11) and / or promyelocytic leukemia(PML)/retinoic acid receptor alpha (RARa) positivity found in the chromosome, variant acute promyelocytic leukemia; With myeloid sarcoma or invasion of central nervous system; NCI CTCAE 4.03 ≥ 2 grade of arrhythmia, or corrected QT interval(QTc )> 450 ms ; patients with a history of torsion or congenital QT prolonged syndrome; active infectious disease judged by the investigator.

Ages Eligible for Study
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Minimum Age: 18 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: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Arm 1:10 mg Arm 2:20 mg Arm 3:40 mg Arm 4:55 mg Arm 5:70 mg
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1<br>Clifutinib Besylate:10 mg | Drug: Clifutinib Besylate<br>* receive oral Clifutinib Besylate once daily until disease progression or unacceptable toxicity occurs, each cycle is defined as 28 days<br>* Other names: HEC73543;|
| Experimental: Arm 2<br>Clifutinib Besylate:20 mg | Drug: Clifutinib Besylate<br>* receive oral Clifutinib Besylate once daily until disease progression or unacceptable toxicity occurs, each cycle is defined as 28 days<br>* Other names: HEC73543;|
| Experimental: Arm 3<br>Clifutinib Besylate:40 mg | Drug: Clifutinib Besylate<br>* receive oral Clifutinib Besylate once daily until disease progression or unacceptable toxicity occurs, each cycle is defined as 28 days<br>* Other names: HEC73543;|
| Experimental: Arm 4<br>Clifutinib Besylate:55 mg | Drug: Clifutinib Besylate<br>* receive oral Clifutinib Besylate once daily until disease progression or unacceptable toxicity occurs, each cycle is defined as 28 days<br>* Other names: HEC73543;|
| Experimental: Arm 5<br>Clifutinib Besylate:70 mg | Drug: Clifutinib Besylate<br>* receive oral Clifutinib Besylate once daily until disease progression or unacceptable toxicity occurs, each cycle is defined as 28 days<br>* Other names: HEC73543;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum tolerated dose (MTD) | Safety and Tolerability assessed through adverse events to determine maximum tolerated dose | day 1-28 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum observed plasma concentration (Cmax) | to assess the pharmacokinetic profile in patients with AML | On day 1,8,15,22,28 | 
| Time of maximum observed plasma concentration (Tmax) | to assess the pharmacokinetic profile in patients with AML | On day 1,8,15,22,28 | 
| Area under the plasma concentration time curve | to assess the pharmacokinetic profile in patients with AML | On day 1,8,15,22,28 | 
| Composite CR rate | CR + CRi +CRMRD- | up to 18 months | 
| Duration of response | The time from receive CR / CRi/CRMRD-/PR to relapse | up to 18 months | 
| Objective response rate | CR + CRi +CRMRD- + PR | up to 18 months | 
| Event Free Survival | From the first time taking experimental drug to treatment failure or progression or relapse or death | up to 18 months | 
| Overall Survival | From the first time taking experimental drug to death | up to 18 months |