Summary

A Phase 1/2, Open-label, Multicenter, Dose Escalation and Expansion Study of the Safety,
Tolerability, Pharmacokinetics, and Pharmacodynamics of Tuspetinib (HM43239) in Patients
with Relapsed or Refractory Acute Myeloid Leukemia (AML)

Objectives

This is a Phase 1/2, open-label, multi-center study to assess the efficacy, safety,
tolerability, pharmacokinetics, including recommended phase 2 dose (RP2D) of tuspetinib
(HM43239) monotherapy in subjects with relapsed or treatment-refractory acute myeloid
leukemia (AML). This study will also evaluate the safety, tolerability, and PK parameters
of tuspetinib (HM43239) in combination with venetoclax when administered in patients with
R/R AML

Eligibility

1. Inclusion Criteria: - Patient is defined as having morphologically documented primary or secondary AML 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 - Patient has an Eastern Cooperative Oncology Group (ECOG) performance status = 2. - Patient'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 at 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, shorter than stated washout period may be considered provided that the patient has recovered from any clinically relevant safety issue and recovered to Grade = 1 toxicity from prior therapies) - Patient must meet the following criteria as indicated on the clinical laboratory tests 1. Serum aspartate aminotransferase(AST) and alanine aminotransferase(ALT) = 2.5× institutional upper limit normal (ULN) 2. Total serum bilirubin = 1.5× institutional ULN 3. Serum creatinine = 1.5× institutional ULN or an estimated glomerular filtration rate (eGFR) of > 45 ml/min as calculated by the Modification of Diet in Renal Disease (MDRD) equation. - Patient is suitable for oral administration of study drug and has minimum life expectancy (= 3 months) - Female patient must be either: - Of non-child bearing 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 highly effective contraception starting at screening and throughout the study period and for 90 days after the final study drug administration. - Female patient must not be breastfeeding at screening and during the study period, and for 90 days after the final study drug administration - Female patient must not donate ova starting at screening and throughout the study period, and for 90 days after the final study drug administration. - Male patient 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 patient must not donate sperm starting at screening and throughout the study period and for 90 days after the final study drug administration. - Patient agrees not to participate in another interventional study while on treatment Exclusion Criteria: Patients must not enter the study if any of the following exclusion criteria are fulfilled. - Patient was diagnosed as acute promyelocytic leukemia (APL) - Patient has BCR-ABL-positive leukemia - Patient has an active malignancy other than AML, or Myelodysplastic Syndrome (MDS). - Patient has persistent non-hematological toxicities of = Grade 2 (CTCAE v4.03), with symptoms and objective findings, from prior AML treatment (including chemotherapy, kinase inhibitors, immunotherapy, experimental agents, radiation, or surgery) - Patient has had hematopoietic stem cell transplant (HSCT) and meets any of the following: 1. Has undergone HSCT within the 2 month period prior to the first study dose 2. Has clinically significant graft-versus-host-disease(GVHD) requiring treatment 3. Has = Grade 2 persistent non-hematological toxicity related to the transplant 4. Has a donor lymphocytes infusion (DLI) = 30 days prior to the first study dose or during the first two cycle of treatment on the study. - Patient has meningeal or central nervous system (CNS) involvement with leukemia or other CNS disease related to underlying and secondary effects of malignancy. - Patient has disseminated intravascular coagulation abnormality (DIC). - Patient has had major surgery within 4 weeks prior to the first study dose. - Patient has had radiation therapy within 4 weeks prior to the first study dose. - 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 or multigated acquisition (MUGA) scan performed within 3 months prior to study entry results in a left ventricular ejection fraction (LVEF) that is = 45%. - Any of the following cardiac abnormalities of history 1. Patient has any clinically important abnormalities in rhythm, conduction or morphology of resting ECG, e.g., complete left bundle branch block, third-degree heart block, second-degree heart block, or PR interval > 250 milliseconds (ms). 2. Patient has a mean QT interval (QTc) by Friderica's method (QTcF) > 450ms in three successive Screening measurements. 3. Patient has any factors that increase the risk of QTc prolongation or risk of arrhythmic events, such as congenital long QT, syndrome, family history of long QT syndrome. 4. Patient is unable or unwilling to discontinue concomitant use of drugs that are known to prolong the QT interval. - Patient is known to have active infection including any identified active COVID-19 infection. - Patient is known to have human immunodeficiency virus infection. - Patient has known active hepatitis B or C, or other active hepatic disorder. - Patient has any condition which, in the investigator's opinion, makes the patient unsuitable for study participation. - Patient has a history of Grade 3 or 4 non-hematologic toxicity related to tyrosine kinase inhibitor.