Clinical Trial to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Tuspetinib (HM43239) in Patients With Relapsed or Refractory Acute Myeloid Leukemia

Study participant is defined as having morphologically documented primary or secondary AML, MDS-IB2 (≥ 10% bone marrow blasts), or CMML by the World Health Organization (WHO) criteria (2016), and fulfills one of the following:

1. Refractory to at least 1 cycle of prior therapy

2. Relapsed after achieving remission with a prior therapy

Study participant has an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.

Study participant's interval from prior treatment to time of study drug administration is at least 2 weeks for cytotoxic agents (except hydroxyurea given for controlling blast cells), at 4 weeks for biologic or cellular immunotherapies, or least 5 half-lives for prior experimental agents or noncytotoxic agents, including immunosuppressive therapy post hematopoietic stem cell transplantation (HSCT). Upon discussion with the Medical Monitor, a shorter than stated washout period may be considered provided that the study participant has recovered from any clinically relevant safety issue and recovered to Grade ≤ 1 toxicity from prior therapies.

Study participant must meet the following criteria as indicated on the clinical laboratory tests.

1. Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3× institutional upper limit normal (ULN)

2. Total serum bilirubin ≤ 1.5× institutional ULN

3. Creatinine clearance as calculated by the Cockcroft-Gault formula or measured by 24-h urine collection of \> 45 mL/min.

Study participant is suitable for oral administration of study drug and has minimum life expectancy (≥ 3 months)

Female study participants must be either:

Of non-childbearing potential

1. Post-menopausal (defined as at least 1 year without any menses) prior to screening, or

2. Documented surgically sterile or status post hysterectomy (at least 1 month prior to screening)

Or, if of childbearing potential,

1. Must have a negative serum or urine pregnancy test at screening (within 72 hours prior to start of treatment), and

2. Must use an acceptable highly effective method of birth control starting at screening and throughout the study period and for 90 days after the final study drug administration.

Female study participants must not be breastfeeding at screening and during the study period, and for 90 days after the final study drug administration

Female study participants must not donate ova starting at screening and throughout the study period, and for 90 days after the final study drug administration.

Male study participants and their female spouse/partners who are of childbearing potential must be using highly effective contraception starting at screening and continue throughout the study period and for 90 days after the final study drug administration.

Male study participants must not donate sperm starting at screening and throughout the study period and for 90 days after the final study drug administration.

Study participant agrees not to participate in another interventional study while on treatment.

Study participant is defined as having morphologically documented newly diagnosed previously untreated primary or secondary AML by the World Health Organization (WHO) criteria (2016) and considered ineligible to receive intensive chemotherapy.

Study participants ≥ 75 years of age are considered ineligible to receive intensive chemotherapy if they meet any of the following criteria:

1. ECOG Performance Status of 2 or 3;

2. Cardiac history of congestive heart failure (CHF) requiring treatment or ejection fraction ≤ 50% or chronic stable angina;

3. Diffusing capacity of the lung for carbon monoxide (DLCO) ≤ 65% or forced expiratory volume during the first second (FEV1) ≤ 65%;

4. Creatinine clearance ≥ 30 mL/min to \< 45 ml/min;

5. Moderate hepatic impairment with total bilirubin \> 1.5 to ≤ 3.0×ULN;

6. Any other comorbidity that the Investigator judges to be incompatible with intensive chemotherapy must be reviewed and approved by the Medical Monitor during screening and prior to treatment.

Study participants are considered ineligible to receive intensive chemotherapy based on their age being ≥ 75 years.

Study participant \< 75 years has an ECOG performance status ≤ 2; study participant ≥ 75 years has an ECOG performance status 0-2.

Study participant must meet the following criteria as indicated on the clinical laboratory tests:

1. Serum AST and ALT ≤ 3× institutional ULN unless considered due to leukemic organ involvement.

2. Total serum bilirubin ≤ 3x institutional ULN unless considered due to leukemic organ involvement for study participants \< 75 years; total serum bilirubin ≤ 1.5x institutional ULN (or ≤ 3x institutional ULN if documented history of Gilbert's syndrome) unless considered due to leukemic organ involvement for study participants ≥ 75 years.

3. Creatinine clearance as calculated by the Cockcroft-Gault formula or measured by 24-h urine collection of ≥ 30 mL/min for study participants \< 75 years; creatinine clearance as calculated by the Cockcroft-Gault formula or measured by 24-h urine collection of ≥ 45 mL/min for study participants ≥ 75 years.