| Eligibility |
Inclusion Criteria:
1. Age=18 years old.
2. Subject has a diagnosis of primary AML or AML secondary to myelodysplastic syndrome
(MDS) according to World Health Organization (WHO) classification as determined by
pathology review at the treating institution.
3. Subject is refractory to or relapsed after prior AML therapy (with or without
hematopoietic stem cell transplant ):
- Advanced relapse after first-line AML therapy is defined as: the patients
achieved Complete remission without minor residual diseases/complete
remission/complete remission with partial hematologic recovery/complete remission
with incomplete hematologic recovery/complete remission with incomplete platelet
recovery/Morphologic leukemia- free state(CRMRD-/CR/CRh/CRi/CRp/MLFS )after
first-line treatment and relapsed after 12 months with hematological relapse;
- Patients with relapsed / refractory AML.
- Refractory to first-line AML therapy is defined as:the patient did not achieve
CRMRD-/CR/CRh/CRi/CRp/MLFS under initial therapy.A subject eligible for standard
therapy must receive at least 1 cycle of an anthracycline containing induction
block in standard dose for the selected induction regimen. A subject not eligible
for standard therapy must have received at least 1 complete block of induction
therapy seen as the optimum choice of therapy to induce remission for this
subject.
- Early relapse:Relapse within 12 months after consolidation therapy after
achieving CRMRD-/CR/CRh/CRi/CRp/MLFS.
- Relapse after 12 months but nonresponse to conventional chemotherapy after
achieving CRMRD-/CR/CRh/CRi/CRp/MLFS.
- Second or more relapse.
- Patients who cannot tolerate intensive chemotherapy develop disease progression
during continuous treatment with low-intensity drugs.
- Persistence of extramedullary leukemia.
4. Patient is positive for FLT3-ITD mutation in bone marrow or whole blood.
5. Eastern Cooperative Oncology Group (ECOG) performance status = 2.
6. Expected survival =12 weeks .
7. Patient must meet the following criteria as indicated on the clinical laboratory
tests:
- Serum creatinine = 1.5 x ULN or an estimated glomerular filtration rate of =50
mL/min .
- Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) = 2.5 x
upper limit of normal (ULN)
- Serum total bilirubin (TBL) = 1.5 x ULN.
- Fridericia's Heart Rate Correction Formula (QTcF) interval =480 msec.
8. Female patients of childbearing potential must have a negative serum pregnancy test
within 14 days prior to the first study drug administration.Female patients of
childbearing potential and male must be surgically sterile or willing to use highly
effective birth control upon enrollment, during the treatment period, and for 6 months
following the last dose of investigational drug.
9. The subject should be willing to provide evidence of valid diagnosis before treatment
or undergo bone marrow puncture or biopsy for diagnosis, and receive bone marrow
puncture or biopsy for efficacy evaluation after treatment.
10. Patients volunteered to participate in this study and signed the informed consent
form.
Exclusion Criteria:
1. Patient was diagnosed as acute promyelocytic leukemia (APL), or Philadelphia
chromosome(BCR-ABL)-positive leukemia (chronic myelogenous leukemia in blast crisis).
2. Patients who received live vaccine (including live attenuated vaccine) within 4 weeks
before randomization and/or planed to receive live vaccine after enrollment.
3. Presence of FLT3-tyrosine kinase domain(TKD) mutation.
4. Patients were prior failed adequate treatment with FLT3 inhibitors.
5. AML with Central Nervous System Leukemia.
6. Patient has AML secondary to prior chemotherapy for other neoplasms, except for MDS.
7. Patients with other malignant tumors past or present,unless whose Disease-free
survival period=5 years.Non-melanin skin cancer, carcinoma in situ, or cervical
intraepithelial neoplastic lesions with completed radical treatment (regardless of
disease-free survival),and subjects with prostate cancer confined to the prostate and
with no evidence of disease recurrence or progression,if they have started hormonal
therapy or have undergone surgery to remove the malignancy or have undergone radical
radiotherapy,will be eligible for the study.
8. Pretrial treatment conditions:
- Patients who received hematopoietic stem cell transplantation within the 2 months
before enrollment,or having clinically significant graft-versus-host disease
(GVHD) or receiving systemic cortisol hormone therapy for GVHD.
- Patients who received chemotherapy, biological therapy, targeted anti-tumor
therapy within 14 days before the first use of the drug in this study or within 5
half-lives of the drug, or radiation therapy within 28 days.
- Patients who participated in other clinical trials and received trial drugs
within 28 days to the first study dose.
- Patients who have had major surgery or significant traumatic injury within 28
days to the first study dose or planted to require major surgery during study
treatment.
9. Concurrent disease conditions:
- Patients are hepatitis B surface antigen or core antibody actives positive,and
hepatitis B virus(HBV) DNA =2000IU/mL or 1×104 copy/mL.
- Patients are hepatitis C virus (HCV) antibody actives positive and HCV-RNA
quantification is above the upper limit of normal at each center.
- Human immunodeficiency virus (HIV) seropositivity.
- Patient has clinically obvious gastrointestinal abnormalities that may affect the
intake, transport, or absorption of drugs (such as inability to swallow, chronic
diarrhea, intestinal obstruction, etc),patients with total gastrectomy or major
gastrectomy (Billroth II), patients with a clear gastrointestinal bleeding
tendency,or major gastrointestinal bleeding considered possible by the
investigator.
- Patient has uncontrolled epilepsy history.
- Patient has uncontrolled hypertension defined as systolic blood pressure greater
than 160 mmHg or diastolic pressure greater than 100 mmHg, despite optimal
medical management and optimal measurement.
- Patient has clinically significant abnormal serum lipase or amylase indicators
during screening.
- Patient has refractory intractable hypokalemia or hypomagnesemia.
- Patient has clinically significant abnormality of coagulation profile, such as
disseminated intravascular coagulation (DIC), hemophilia.
- Patient has congestive heart failure New York Heart Association (NYHA) class 3 or
4 or patient with a history of congestive heart failure NYHA class 3 or 4 in the
past, unless a screening echocardiogram performed within 1 month before study
entry results in a left ventricular ejection fraction that is = 45%.
- Patients with second degree (Mobitz II) or third degree atrioventricular block
disease (except for patients who use the pacemaker) or complete left bundle
branch block.
- Patients with new clinically significant arrhythmias (except for sinus
tachycardia caused by anemia, infection and AML) or patients with previous
arrhythmias that require long-term use of drugs with QT-prolonging effects.
- Patients with any one of the following diseases within 6 months prior to
randomization:myocardial infarction,unstable angina pectoris,Patients undergoing
coronary artery bypass graft(CABG) or peripheral artery bypass
implantation,congestive heart-failure,Cerebrovascular events (including cerebral
hemorrhage and cerebral infarction, etc.),Deep venous thrombosis (except for deep
venous thrombosis due to peripherally inserted central venous catheter (PICC)
catheterization),pulmonary embolism and other diseases that the researcher
considers inappropriate to participate in this study.
- Patients with diagnosed or suspected long QT syndrome at screening (including a
family history of long QT syndrome).
- Patient has an active uncontrolled infection.
- Patient has severe unhealed wounds, ulcers, or fractures.
- Females who are pregnant or breastfeeding.
- Patients are not suitable for the study in the investigator's opinion.
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