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

Study Overview
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Brief Summary
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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)

Detailed Description
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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

Official Title
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A Phase 1/2 Open Label, Multicenter, Dose Escalation and Expansion Study of the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of HM43239 in Patients With Relapsed or Refractory Acute Myeloid Leukemia (AML)

Conditions
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Relapsed or Refractory Acute Myeloid Leukemia

Intervention / Treatment
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* Drug: Tuspetinib
* Drug: Venetoclax Oral Tablet


Participation Criteria
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Eligibility Criteria
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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: Refractory to at least 1 cycle of prior therapy 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 Serum aspartate aminotransferase(AST) and alanine aminotransferase(ALT) ≤ 2.5× institutional upper limit normal (ULN) Total serum bilirubin ≤ 1.5× institutional ULN 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 Post-menopausal (defined as at least 1 year without any menses) prior to screening, or Documented surgically sterile or status post hysterectomy (at least 1 month prior to screening) Or, if of childbearing potential, Must have a negative serum or urine pregnancy test at screening (within 72 hours prior to start of treatment), and 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: Has undergone HSCT within the 2 month period prior to the first study dose Has clinically significant graft-versus-host-disease(GVHD) requiring treatment Has ≥ Grade 2 persistent non-hematological toxicity related to the transplant 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 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). Patient has a mean QT interval (QTc) by Friderica's method (QTcF) > 450ms in three successive Screening measurements. 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. 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Three parts in the study - Part A (dose escalation, tuspetinib as a single agent), Part B (dose exploration, tuspetinib as a single agent), Part C (dose expansion, tuspetinib as a single agent and combo arm of tuspetinib with venetoclax)
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part A Dose Escalation<br>For Part A (tuspetinib as a single agent), dose escalation cohort is planned up to 6 dose levels. If a subject in the dose escalation cohort at any dose level achieves clinical response then the dose level will continue to enroll in Part B. If one DLT or less is observed in the 6 patients (<1/6 DLT observed) in Part A, up to 20 evaluable patients can be enrolled in Part B at that dose level. | Drug: Tuspetinib<br>* Daily (QD), continuous dosing<br>* Other names: HM43239;|
| Experimental: Part B Dose Exploration<br>For Part B (tuspetinib as a single agent), dose exploration cohort is planned up to 4 dose levels. | Drug: Tuspetinib<br>* Daily (QD), continuous dosing<br>* Other names: HM43239;|
| Experimental: Part C Dose Expansion (tuspetinib as a single agent)<br>Part C, dose expansion, consists of 2 arms (tuspetinib as a single agent or tuspetinib plus venetoclax). Patients will be randomly assigned to either arm based on the number of slots available. The initial tuspetinib dose for the single arm will be 120mg. | Drug: Tuspetinib<br>* Daily (QD), continuous dosing<br>* Other names: HM43239;|
| Experimental: Part C Dose Expansion (Combination Arm - tuspetinib and venetoclax)<br>Part C, dose expansion, consists of 2 arms (tuspetinib or tuspetinib plus venetoclax). Patients will be randomly assigned to either arm based on the number of slots available. The initial tuspetinib dose for the combo arm will be 80mg. | Drug: Tuspetinib<br>* Daily (QD), continuous dosing<br>* Other names: HM43239;Drug: Venetoclax Oral Tablet<br>* Venetoclax will be given to patients in combo treatment group (Part C) either in 50 mg or 100 mg tablets<br>* Other names: Venetoclax;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Recommended Phase 2 dose | To determine the recommended phase 2 dose based on safety, efficacy, pharmacokinetics (PK), and pharmacodynamics (PD) consideration | 4 years | 
| Safety of HM43239 | Determine the maximum tolerated dose at which no more than 1 out of 6 patients experience a dose-limiting toxicity or establish the safety of clinically effective dose below the MTD if the MTD is not reached.relapsed or treatment-refractory (R/R) AML | 4 years | 
| Tolerability of HM43239 | To determine the frequency and severity of drug-related adverse events across different dose levels when administered in patients with R/R AML | 4 years | 
| Safety of HM43239 in combination with venetoclax | Determine the maximum tolerated dose of HM43239 in combination with venetoclax at which no more than 1 out of 6 patients experience a dose-limiting toxicity or establish the safety of clinically effective dose below the MTD if the MTD is not reached.relapsed or treatment-refractory (R/R) AML | 4 years | 
| Tolerability of HM43239 in combination with venetoclax | To determine the frequency and severity of drug-related adverse events across different dose levels of HM43239 in combination with venetoclax when administered in patients with R/R AML | 4 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Anti-leukemic activity of HM43239 | To investigate the rate of complete remission (CR), CR with partial hematologic recovery (CRh), CR with incomplete platelet recovery (CRp), CR with incomplete hematologic recovery (CRi), and partial remission (PR) of patients taking HM43239 | 4 years | 
| Anti-leukemic activity of HM43239 in combination with venetoclax | To investigate the rate of complete remission (CR), CR with partial hematologic recovery (CRh), CR with incomplete platelet recovery (CRp), CR with incomplete hematologic recovery (CRi), and partial remission (PR) of patients taking HM43239 in combination with venetoclax | 4 years | 
| Pharmacokinetic variables including maximum plasma concentration (Cmax) | Pharmacokinetic variables including maximum plasma concentration (Cmax) | Cycle 1 (at least 28 days) | 
| Pharmacokinetic variables including minimum plasma concentration (Cmin) | Pharmacokinetic variables including minimum plasma concentration (Cmin) | Cycle 1 (at least 28 days) | 
| Pharmacokinetic variables including area under the curve (AUC) | Pharmacokinetic variables including area under the curve (AUC) | Cycle 1 (at least 28 days) | 
| Pharmacokinetic variables including volume of distribution | Pharmacokinetic variables including volume of distribution | Cycle 1 (at least 28 days) | 
| Pharmacokinetic variables including clearance | Pharmacokinetic variables including clearance | Cycle 1 (at least 28 days) | 
| Pharmacodynamic variables | Determine PD variables by using a plasma inhibitory activity assay (PIA assay) examining the reduction in phospho-STAT5 and phospho-FLT3 in cell lines exposed to plasma from subjects treated in the study. | 4 years |