A Study of XY0206 Tablets in Patients With Relapsed / Refractory Acute Myeloid Leukemia

A Multicenter, Open, Dose Increasing Phase I Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Primary Efficacy of xy0206 Tablets in Relapsed / Refractory Acute Myeloid Leukemia Subjects

1. To evaluate the safety and tolerability of xy0206 as single drug in the treatment of relapsed / refractory AML;
2. Evaluate the dose limited toxicity (DLT) and maximum tolerable dose (MTD) of xy0206 as single drug in the treatment of relapsed / refractory AML subjects.
3. To evaluate the pharmacokinetic (PK), pharmacokinetic (PD) characteristics and PK / PD correlation of xy0206 as single drug treatment in relapsed / refractory AML subjects;
4. To evaluate the primary efficacy of xy0206 as single drug in the treatment of relapsed / refractory AML patients;
5. To evaluate biomarkers of xy0206 as single drug treatment for relapsed / refractory AML subjects.

Inclusion Criteria:

• Patients must meet all of the following criteria before entering the group:

  1. At least 18 years old; 2. Based on the World Health Organization (WHO) 2016 classification, the patients who were confirmed by the morphology of bone marrow cells and met the diagnosis criteria of relapsed / refractory AML (refer to the Chinese diagnosis and treatment guidelines for relapsed and refractory acute myeloid leukemia (2017 version)), the diagnosis criteria of relapsed AML: after CR, the peripheral blood once again showed leukemia cells or the original / immature cells in bone marrow were more than 5% (except the bone marrow after consolidated chemotherapy) The diagnosis standard of refractory AML: the primary refractory disease that has not been completely relieved after two courses of chemotherapy induced by standard regimen (including cytarabine and an anthracycline or anthraquinone drug); 3. ECOG physical fitness score is ≤ 2 points ; 4 Estimated survival time ≥ 12 weeks; 5 The organ function level of subjects must meet the following requirements:

  • Blood routine test: WBC ≤ 30 × 109 / L (it is allowed to take hydroxyurea until 3 days before administration of test drug to stabilize WBC);
  • Blood biochemistry: serum creatinine (Scr) ≤ 1.5 × ULN or creatinine clearance rate (Ccr) ≥ 60 ml / min (using Cockcroft -Gault formula); alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP) ≤ 2.5 × ULN (liver with leukemia cell infiltration ≤ 5 × ULN), total bilirubin (TBIL) ≤ 1.5 × ULN;
  • Electrolyte: the content of potassium, sodium, calcium and magnesium in the blood is within the normal value range of the laboratory (if the abnormal laboratory result judged by the researcher is of no clinical significance or can be controlled within the normal value range by drugs in the screening period, the subject can be included in the group);
  • Coagulation function: INR ≤ 1.5 × ULN, APTT < 10 seconds, PT < 3 seconds, FIB ≥ 1.5g/l (blood products or drugs are allowed to be corrected 3 days before administration of test drugs);
  • Friderica corrected QT value (QTC) for male ≤ 450 ms or female ≤ 470 MS;
  • LVEF≥ 50%；
  • Urinary protein < 2 + was detected in urine routine. If urinary protein ≥ 2 +, 24-hour urinary protein quantification is needed, and only when 24-hour urinary protein < 2g can be enrolled in the group; 6. The serum pregnancy test must be carried out within 28 days before receiving the first dose of study drug and the result must be negative. The women of childbearing age and the male subjects agree to adopt the routine and effective contraceptive measures during the whole study period and within 6 months after the treatment; 7. The subjects should be willing to provide effective diagnosis evidence before treatment or accept bone marrow puncture or biopsy for diagnosis, and accept bone marrow puncture or biopsy for efficacy evaluation after treatment; 8. Volunteer to participate in clinical research and sign informed consent in writing.

Exclusion Criteria:

• Patients cannot participate in this clinical study if they meet any of the following conditions:

  1. Known allergy to the study drug or any of its ingredients; has been treated with sunitinib malate, or allergy to sunitinib malate;

  2. BCR / ABL positive leukemia (chronic myeloid leukemia);

  3. The subjects had central nervous system leukemia;

  4. The subjects had secondary AML after chemotherapy for other tumors (except MDS);

  5. At the same time, patients with other malignant tumors (except for those with cured stage IB or lower grade cervical cancer, non-invasive basal cell or squamous cell skin cancer, malignant melanoma with complete remission (CR) > 10 years, and other malignant tumors with complete remission (CR) > 5 years);

  6. Treatment before the trial:

     • Previous treatment with FLT3 inhibitor;
     • Patients who have received allogeneic hematopoietic stem cell transplantation before;
     • Received chemotherapy, biotherapy, targeted antitumor therapy within 28 days before starting to use the study drug, and radiotherapy within 14 days;
     • Drugs with significant effect on P450 metabolic enzyme pathway taken within 2 weeks before the screening period;
     • Have participated in other clinical studies and applied research drugs within 28 days before starting to use research drugs;
     • Major surgery or significant traumatic injury within 28 days prior to the first administration of the study treatment or maybe major surgery is needed during the study treatment period;
     • Concomitant drugs that may cause QTc prolongation or induce torsade de pointes (TdP) are required, in addition to antimicrobials used as standard therapy for the prevention or treatment of infection and other such drugs considered essential by the researchers;

  7. The toxic and side effects caused by previous treatment did not recover to CTCAE ≤ 1, except for hair loss and other tolerable events judged by the researchers;

  8. Combined diseases:

     • One or more HBsAg, HCV, anti HIV or anti Treponema pallidum specific antibodies are positive;
     • Clinically significant gastrointestinal abnormalities that may affect drug intake, transport or absorption (e.g., inability to swallow, chronic diarrhea, intestinal obstruction, peptic ulcer, etc.), subjects with total gastrectomy, or patients with malabsorption syndrome;
     • Have a history of uncontrolled epilepsy, central nervous system disease or mental illness;
     • Hypertension with poor drug control (persistent systolic blood pressure ≥ 150 mmHg and / or diastolic blood pressure ≥ 100 mmHg despite antihypertensive treatment);
     • Poorly controlled diabetes mellitus (fasting blood glucose continues to be > 7.1mmol/L despite hypoglycemic treatment), or insulin-dependent diabetes mellitus (type I diabetes), or non insulin-dependent diabetes mellitus with small vessel disease, or pancreatic dysfunction;
     • In the 12 months before the first application, there were any of the following conditions: symptomatic congestive heart failure (New York Heart Association class II-IV), uncontrolled arrhythmia, angina pectoris, myocardial infarction, stroke (except lacunar infarction), coronary / peripheral artery bypass surgery, pulmonary embolism;
     • Long QT syndrome with congenital long QT interval syndrome or known family history;
     • There is a history of LVEF falling below 40%;
     • Uncontrolled active infections (bacteria, viruses, fungi, etc.);
     • Bleeding grade ≥ grade 3 ;
     • Have adrenal insufficiency;
     • The thyroid function was abnormal in the past, or could not be maintained in the normal range even under the condition of drug treatment;
     • Currently, there are serious unhealed wounds, ulcers or fractures;
     • Stevens Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN);

  9. For female subjects: currently in pregnancy or lactation;

  10. Any previous or current disease, treatment, or laboratory abnormality that may interfere with the results of the study, affect the subject's participation in the whole process of the study, or the subject is not suitable for the study in the opinion of the investigator.