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

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)

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)

Study Overview

• Status: Recruiting
• Conditions: Relapsed or Refractory Acute Myeloid Leukemia
• Intervention / Treatment: Drug: Tuspetinib; Drug: Venetoclax Oral Tablet

Detailed 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

• Study Type: Interventional
• Enrollment (Estimated): 218
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Rafael Bejar, MD, PhD; Phone Number: 858-401-6852; Email: rbejar@aptose.com

Study Locations

• Australia
  • New South Wales
    • Albury, New South Wales, Australia, 2640
      • Recruiting
      • Border Medical Oncology
      • Contact: Anish Puliyayil, MD; Email: apuliyayil@bordermedonc.com.au
      • Principal Investigator: Anish Puliyayil, MD
  • Queensland
    • Herston, Queensland, Australia, 4006
      • Recruiting
      • Royal Brisbane and Women'S Hospital
      • Contact: Steven Lane, MD
      • Principal Investigator: Steven Lane, MD
    • Townsville, Queensland, Australia, 4812
      • Recruiting
      • Townsville University hospital
      • Contact: Hock-Choong Lai, MD; Email: Hock.lai@health.qld.gov.au
      • Principal Investigator: Hock-Choong Lai, MD
  • Victoria
    • Fitzroy, Victoria, Australia, 3065
      • Recruiting
      • St Vincent's Hospital Melbourne
      • Contact: Shuhying Tan, MD; Email: ShuhYing.TAN@svha.org.au
      • Principal Investigator: Shuhying Tan, MD
  • Western Australia
    • Nedlands, Western Australia, Australia, 6009
      • Recruiting
      • Sir Charles Gairdner Hospital
      • Principal Investigator: Carolyn Grove, MD
      • Contact: Carolyn Grove, MD; Email: carolyn.grove@health.wa.gov.au
• Germany
  • Berlin, Germany, 13353
    • Recruiting
    • Charité Universitätsmedizin Berlin
    • Contact: Jörg Westermann, MD; Email: joerg.westermann@charite.de
    • Principal Investigator: Jörg Westermann, MD
  • Saxony
    • Leipzig, Saxony, Germany, 04103
      • Recruiting
      • Universitätsklinikum Leipzig
      • Principal Investigator: Uwe Platzbecker, MD
      • Contact: Uwe Platzbecker, MD; Email: uwe.platzbecker@medizin.uni-leipzig.de
• Korea, Republic of
  • Daegu, Korea, Republic of, 41944
    • Recruiting
    • Kyungpook National University Hospital
    • Contact: Sang-Kyun Sohn
  • Pusan, Korea, Republic of, 49241
    • Recruiting
    • Pusan National University Hospital
    • Contact: Ho-Jin Shin
  • Seongnam, Korea, Republic of, 13620
    • Recruiting
    • Seoul National University Bundang Hospital
    • Contact: Jeong-Ok Lee
  • Seoul, Korea, Republic of, 03080
    • Active, not recruiting
    • Seoul National University Hospital
  • Seoul, Korea, Republic of, 05505
    • Recruiting
    • Asan Medical Center
    • Contact: Yunksuk Choi, MD; Phone Number: +82-2-3010-3292; Email: choiysmd@gmail.com
  • Seoul, Korea, Republic of, 06351
    • Recruiting
    • Samsung Medical Center
    • Contact: Chul-Won Jung; Phone Number: +82-2-3410-2980; Email: chulwon1.jung@samsung.com
• New Zealand
  • Auckland
    • Grafton, Auckland, New Zealand, 1023
      • Recruiting
      • Auckland City Hospital
      • Contact: Leanne Berkahn, MD; Email: LeanneBerk@adhb.govt.nz
      • Principal Investigator: Leanna Berkahn, MD
• Spain
  • Barcelona, Spain, 08035
    • Recruiting
    • Hospital Universitario Vall d'Hebron
    • Contact: Olga Salamero, MD; Email: osalamero@vhio.net
    • Principal Investigator: Olga Salamero
  • Valencia, Spain, 46010
    • Recruiting
    • Hospital Clínico Universitario de Valencia
    • Contact: Maria Tormo, MD; Email: tormo_mar@gva.es
    • Principal Investigator: Maria Tormo, MD
  • Valencia, Spain, 46026
    • Recruiting
    • Hospital Universitari i Politecnic La Fe
    • Principal Investigator: Pau Montesinos, MD
    • Contact: Pau Montesinos, MD; Email: montesinos_pau@gva.es
  • Asturias
    • Oviedo, Asturias, Spain, 33011
      • Recruiting
      • Hospital Universitario Central de Asturias
      • Principal Investigator: Teresa Bernal
      • Contact: Teresa Bernal; Email: bernaldelcastillo@gmail.com
  • Madrid
    • Pozuelo De Alarcón, Madrid, Spain, 28223
      • Recruiting
      • Hospital Quiron Madrid
      • Contact: Carmen Martinez Chamorro, MD; Email: carmen.chamorro@quironsalud.es
      • Principal Investigator: Carmen Martinez Chammoro
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35233
      • Recruiting
      • The Kirklin Clinic of Uab Hospital
      • Contact: Pankit Vachhani, MD; Email: jsregister@uabmc.edu
  • California
    • Duarte, California, United States, 91010
      • Active, not recruiting
      • City of Hope Comprehensive Cancer Center
    • Irvine, California, United States, 92697
      • Recruiting
      • University of California Irvine
      • Principal Investigator: Deepa Jeyakumar, MD
      • Contact: Deepa Jeyakumar, MD; Email: djeyakum@hs.uci.edu
    • La Jolla, California, United States, 92093
      • Recruiting
      • UCSD Moores Cancer Center
      • Principal Investigator: Carolyn Mulroney, MD
      • Contact: Carolyn Mulroney, MD; Email: camulroney@health.ucsd.edu
    • Los Angeles, California, United States, 90033
      • Recruiting
      • USC/Norris Comprehensive Cancer Center
      • Contact: Eric Tam, MD; Email: eric.tam@med.usc.edu
      • Principal Investigator: Eric Tam, MD
    • Palo Alto, California, United States, 94304
      • Recruiting
      • Stanford Cancer Center
      • Principal Investigator: Gabriel Mannis, MD
      • Contact: Gabriel Mannis, MD; Email: gmannis@stanford.edu
    • Sacramento, California, United States, 95817
      • Recruiting
      • University of California, Davis
      • Contact: Brian Jonas; Phone Number: 916-703-9151; Email: bajonas@ucdavis.edu
  • Connecticut
    • New Haven, Connecticut, United States, 06520
      • Recruiting
      • Yale University
      • Contact: Nikolai Podoltsev, MD; Email: nikolai.podoltsev@yale.edu
      • Principal Investigator: Nikolai Podoltsev, MD, PhD
  • Florida
    • Miami, Florida, United States, 33136
      • Recruiting
      • University of Miami - Miller School of Medicine
      • Contact: Justin Watts, MD; Email: jxw401@miami.edu
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Recruiting
      • Emory University
      • Contact: Martha Arellano; Phone Number: 404-712-0720; Email: marella@emory.edu
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Recruiting
      • Massachusetts General Hospital
      • Contact: Amir Fathi, MD
  • North Carolina
    • Durham, North Carolina, United States, 27705
      • Recruiting
      • Duke University Medical Center
      • Contact: Harry Erba, MD; Email: harry.erba@duke.edu
  • Ohio
    • Cleveland, Ohio, United States, 44106
      • Recruiting
      • Cleveland Clinic - Taussig Cancer Center
      • Contact: Studipto Mukherjee, MD; Email: mukhers2@ccf.org
      • Principal Investigator: Studipto Mukherjee, MD
    • Columbus, Ohio, United States, 43210
      • Recruiting
      • The Ohio State University Wexner Medical Center
      • Principal Investigator: Uma Borate, MD
      • Contact: Uma Borate, MD; Email: uma.borate@osumc.edu
  • Texas
    • Houston, Texas, United States, 77030
      • Recruiting
      • MD Anderson Cancer Center
      • Contact: Naval Daver, Dr; Phone Number: 713-792-6477; Email: NDaver@mdanderson.org

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Part A Dose Escalation; 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; Daily (QD), continuous dosing; Other Names: HM43239
Experimental: Part B Dose Exploration; For Part B (tuspetinib as a single agent), dose exploration cohort is planned up to 4 dose levels.	Drug: Tuspetinib; Daily (QD), continuous dosing; Other Names: HM43239
Experimental: Part C Dose Expansion (tuspetinib as a single agent); 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; Daily (QD), continuous dosing; Other Names: HM43239
Experimental: Part C Dose Expansion (Combination Arm - tuspetinib and venetoclax); 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; Daily (QD), continuous dosing; Other Names: HM43239; Drug: Venetoclax Oral Tablet; Venetoclax will be given to patients in combo treatment group (Part C) either in 50 mg or 100 mg tablets; Other Names: Venetoclax

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Aptose Biosciences Inc.
• Investigators: Principal Investigator: Naval Daver, MD, M.D. Anderson Cancer Center

Study record dates

Study Major Dates

• Study Start (Actual): March 11, 2019
• Primary Completion (Estimated): February 1, 2024
• Study Completion (Estimated): August 1, 2024

Study Registration Dates

• First Submitted: January 28, 2019
• First Submitted That Met QC Criteria: February 20, 2019
• First Posted (Actual): February 22, 2019

Study Record Updates

• Last Update Posted (Actual): December 7, 2023
• Last Update Submitted That Met QC Criteria: December 5, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Antineoplastic Agents; Venetoclax
• Other Study ID Numbers: HM-FLTI-101

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No