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

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.

• Clifutinib Besylate (Drug), also known as HEC73543: receive oral Clifutinib Besylate once daily until disease progression or unacceptable toxicity occurs, each cycle is defined as 28 days

Primary outcomes

• Maximum tolerated dose (MTD) [day 1-28]: Safety and Tolerability assessed through adverse events to determine maximum tolerated dose

Secondary outcomes

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

Sex: All, ages: 18 Years to any

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.

• Jie Jin, Doctor, Study chair, First Affiliated Hospital of Zhejiang University