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

Relapsed or Refractory Acute Myeloid Leukemia Clinical Trial

— APTIVATE  

Official title:

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)

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03850574
• Other study ID #: HM-FLTI-101
• Status: Recruiting
• Phase: Phase 1/Phase 2
• Start date: March 11, 2019
• Est. completion date: August 2024

Study information

• Verified date: October 2023
• Source: Aptose Biosciences Inc.
• Contact: Rafael Bejar, MD, PhD
• Phone: 858-401-6852
• Email: rbejar[@]aptose.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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)

Description:

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

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 218
• Est. completion date: August 2024
• Est. primary completion date: February 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Leukemia
• Leukemia, Myeloid
• Leukemia, Myeloid, Acute
• Relapsed or Refractory Acute Myeloid Leukemia

Intervention

Drug:
• Tuspetinib
Daily (QD), continuous dosing
• Venetoclax Oral Tablet
Venetoclax will be given to patients in combo treatment group (Part C) either in 50 mg or 100 mg tablets

Locations

Country	Name	City	State
Australia	Border Medical Oncology	Albury	New South Wales
Australia	St Vincent's Hospital Melbourne	Fitzroy	Victoria
Australia	Royal Brisbane and Women's Hospital	Herston	Queensland
Australia	Sir Charles Gairdner Hospital	Nedlands	Western Australia
Australia	Townsville University Hospital	Townsville	Queensland
Germany	Charité Universitätsmedizin Berlin	Berlin
Germany	Universitätsklinikum Leipzig	Leipzig	Saxony
Korea, Republic of	Kyungpook National University Hospital	Daegu
Korea, Republic of	Pusan National University Hospital	Pusan
Korea, Republic of	Seoul National University Bundang Hospital	Seongnam
Korea, Republic of	Asan Medical Center	Seoul
Korea, Republic of	Samsung Medical Center	Seoul
Korea, Republic of	Seoul National University Hospital	Seoul
New Zealand	Auckland City Hospital	Grafton	Auckland
Spain	Hospital Universitario Vall d'Hebron	Barcelona
Spain	Hospital Universitario Central de Asturias	Oviedo	Asturias
Spain	Hospital Quirón Madrid	Pozuelo De Alarcón	Madrid
Spain	Hospital Clinico Universitario de Valencia	Valencia
Spain	Hospital Universitari i Politècnic La Fe	Valencia
United States	Emory University	Atlanta	Georgia
United States	The Kirklin Clinic of UAB Hospital	Birmingham	Alabama
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	Cleveland Clinic - Taussig Cancer Center	Cleveland	Ohio
United States	The Ohio State University Wexner Medical Center	Columbus	Ohio
United States	City of Hope Comprehensive Cancer Center	Duarte	California
United States	Duke University Medical Center	Durham	North Carolina
United States	MD Anderson Cancer Center	Houston	Texas
United States	University of California Irvine	Irvine	California
United States	UCSD Moores Cancer Center	La Jolla	California
United States	USC/Norris Comprehensive Cancer Center	Los Angeles	California
United States	University of Miami - Miller School of Medicine	Miami	Florida
United States	Yale University	New Haven	Connecticut
United States	Stanford Cancer Center	Palo Alto	California
United States	University of California, Davis	Sacramento	California

Sponsors (1)

Lead Sponsor	Collaborator
Aptose Biosciences Inc.

Countries where clinical trial is conducted

United States,  Australia,  Germany,  Korea, Republic of,  New Zealand,  Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Recommended Phase 2 dose	To determine the recommended phase 2 dose based on safety, efficacy, pharmacokinetics (PK), and pharmacodynamics (PD) consideration	4 years
Primary	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
Primary	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
Primary	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
Primary	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	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
Secondary	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
Secondary	Pharmacokinetic variables including maximum plasma concentration (Cmax)	Pharmacokinetic variables including maximum plasma concentration (Cmax)	Cycle 1 (at least 28 days)
Secondary	Pharmacokinetic variables including minimum plasma concentration (Cmin)	Pharmacokinetic variables including minimum plasma concentration (Cmin)	Cycle 1 (at least 28 days)
Secondary	Pharmacokinetic variables including area under the curve (AUC)	Pharmacokinetic variables including area under the curve (AUC)	Cycle 1 (at least 28 days)
Secondary	Pharmacokinetic variables including volume of distribution	Pharmacokinetic variables including volume of distribution	Cycle 1 (at least 28 days)
Secondary	Pharmacokinetic variables including clearance	Pharmacokinetic variables including clearance	Cycle 1 (at least 28 days)
Secondary	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