This is a dose-escalation phase I trial to evaluate the safety and tolerability of MAX-40279
in subjects with acute myelogenous leukemia(AML).
The class III receptor tyrosine kinase FMS-related tyrosine kinase 3 (FLT3), is mutated and
activated in about 30% of adult patients with AML. The mutations involve either an internal
tandem duplication (ITD) (in about 25% of AML patients) or a point mutation in the tyrosine
kinase domain (TKD) (in about 7% of patients). Patients with mutations in FLT3, particularly
those with ITD mutations, have a worse prognosis, with lower rate of complete remission, and
lower overall survival . Thus, inhibition of activated FLT3 kinase by a pharmacologic agent
is an attractive therapeutic strategy in AML.
The aberrant of fibroblast growth factor receptor (FGFR) might be a major reason fot
resistance to targeted therapies, and FGFR inhibitors significantly suppress leukemia
development in vivo.
MAX-40279 is a dual inhibitor of FLT3 and FGFR. Our goal is to develpe this uqiue dual
inhibitor to be a more effective and wider use for AML treatment than the current known FLT3
inhibitors.
Inclusion Criteria:
1. Males and/or females over age 18
2. Ability to understand the purposes and risks of the trial and signed informed consent
forms approved by the investigator's Institutional Review Board (IRB)/Independent
Ethics Committee (IEC) of the trial site was obtained before the entering the trial
3. Subject has morphologically documented primary AML or AML secondary to myelodysplastic
syndrome (MDS) as defined by the World Health Organization (WHO) criteria for which no
established standard therapy is available
4. ECOG performance status of 0 to 2
5. Persistent chronic clinically significant nonhematological toxicities from prior
treatment (including chemotherapy, kinase inhibitors, immunotherapy, experimental
agents, radiation, HSCT, or surgery) must be Grade ≤ 1
6. In the absence of rapidly progressing disease clearly documented by the investigator,
the interval from prior treatment to time of MAX-40279 administration will be at least
2 weeks (14 days) for prior cytotoxic agents or at least 5 half-lives for prior
noncytotoxic agents, including immunosuppressive therapy post HSCT
7. Acceptable liver function defined below:
- Total bilirubin ≤ 1.5 times upper limit of normal range (ULN)
- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 times
ULN;
8. Acceptable renal function defined below:
• Serum creatinine ≤ 1.5 times ULN or calculated creatinine clearance (by the
Cockcroft-Gault formula) ≥ 60 mL/min
9. Acceptable coagulation status defined below:
- Prothrombin time < 1.3 times ULN
- Partial thrombin time < 1.3 times ULN
10. No clinically significant abnormalities in urinalysis
11. Female participants of child bearing potential agree not to be pregnant or lactating
during the study and for three months following the last dose of study drug. Both men
and women of reproductive potential must agree to use a highly effective method of
birth control during the study and for three months following the last dose of study
drug. A highly effective method of contraception is defined as one that results in a
low failure rate, i.e., less than 1% per year, when used consistently and correctly
Exclusion Criteria:
1. Disease diagnosis of acute promyelocytic leukemia
2. Previously treated malignancies other than the current disease, except for adequately
treated non-melanoma skin cancer, in situ cancer, or other cancer from which the
subject has been disease-free for at least 5 years at the trial entry
3. Active, uncontrolled bacterial, viral, or fungal infections, requiring systemic
therapy
4. Major surgery, other than diagnostic surgery, within 4 weeks prior to the trial entry,
without complete recovery
5. Percutaneous coronary intervention conducted within 6 months prior to the trial entry
for cardiac infarction or angina pectoris
6. Seizure disorders requiring anticonvulsant therapy
7. Taking a medication that prolongs QT interval and has a risk of Torsades de Pointes，or
a history of long QT syndrome
8. Medical history of difficulty swallowing, malabsorption or other chronic
gastrointestinal disease, or conditions that may hamper compliance and/or absorption
of the tested product
9. Participation in an investigational drug or device trial within 4 weeks prior to the
trial entry
10. Known infection with human immunodeficiency virus (HIV), hepatitis B, or hepatitis C
11. Recent venous thrombosis (including deep vein thrombosis or pulmonary embolism within
1 year of study)
12. History of upper gastrointestinal hemorrhage, peptic ulcer disease, or bleeding
diathesis
13. Subject is pregnant (positive serum beta human chorionic gonadotropin [β-HCG] test at
screening) or is currently breast-feeding, their partner anticipates becoming
pregnant/impregnating during the trial or within 6 months after receiving the last
dose of trial treatment
14. Concomitant disease or condition that could interfere with the conduct of the trial,
or that would, in the opinion of the Investigator, pose an unacceptable risk to the
subject in this trial
15. Unwillingness or inability to comply with the trial protocol for any reason
16. Legal incapacity or limited legal capacity
17. Cardiac disease with New York Heart Association (NYHA) Class III or IV, including
congestive heart failure, myocardial infarction within 6 months prior to the trial
entry, unstable arrhythmia, or symptomatic peripheral arterial vascular
