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

NCT03850574 | Recruiting Phase 1 FDA Drug

• 3 other identifiers: HM-FLTI-1012023-503244-14-002022-002826-29
• Study Type: interventional
• Target: 240
• Locations: 6 countries
• Sites: 34

Brief Summary

The main purpose of this study is to identify a safe and potentially effective dose of tuspetinib to be used in future studies in study participants diagnosed with acute myeloid leukemia (AML), myelodysplastic syndromes with increased blasts grade 2 (MDS-IB2), or chronic myelomonocytic leukemia (CMML) that is relapsed or refractory after at least one line of prior therapy, or in study participants with newly diagnosed AML. Tuspetinib will be administered as a single agent or in combination with other drugs (venetoclax or venetoclax plus azacitidine), as specified for each part of the study.

Conditions

Leukemia, Myeloid, Acute; Refractory AML; Relapsed Adult AML; Myelodysplastic Syndrome With Excess Blasts-2; Chronic Myelomonocytic Leukemia

Keywords

Tuspetinib; Acute Myeloid Leukemia; AML; Relapsed; Refractory; Myelodysplastic Syndromes with Increased Blasts Grade 2; MDS-IB2; Chronic Myelomonocytic Leukemia; CMML; Venetoclax; Azacitidine; Newly Diagnosed

Outcome Measures

Primary Outcomes (10)

• Frequency and severity of drug-related adverse events

  4 years

• Maximum tolerated dose (MTD) of tuspetinib

  The MTD will be determined as the dose at which no more than 1 out of 6 study participants experiences a dose-limiting toxicity (DLT). Alternatively, the safety of a clinically effective dose below the MTD will be established if the MTD is not reached in study participants.

  4 years

• Maximum plasma concentration (Cmax)

  Maximum plasma concentration (Cmax) will be summarized by cohort using descriptive statistics including number of study participants, mean, standard deviation, minimum, median, maximum, geometric mean, and coefficient of variation (CV) of the mean and geometric mean. Time-course of drug concentrations will be plotted as appropriate.

  Cycle 1 (at least 28 days)

• Minimum plasma concentration (Cmin)

  Minimum plasma concentration (Cmin) will be summarized by cohort using descriptive statistics including number of study participants, mean, standard deviation, minimum, median, maximum, geometric mean, and coefficient of variation (CV) of the mean and geometric mean. Time-course of drug concentrations will be plotted as appropriate.

  Cycle 1 (at least 28 days)

• Area under the plasma concentration-time curve (AUC)

  Area under the plasma concentration-time curve (AUC) for various timepoints will be summarized by cohort using descriptive statistics including number of study participants, mean, standard deviation, minimum, median, maximum, geometric mean, and coefficient of variation (CV) of the mean and geometric mean. Time-course of drug concentrations will be plotted as appropriate.

  Cycle 1 (at least 28 days)

• Time to maximum concentration (Tmax)

  Time to maximum concentration (Tmax) will be summarized by cohort using descriptive statistics including number of study participants, mean, standard deviation, minimum, median, maximum, geometric mean, and coefficient of variation (CV) of the mean and geometric mean. Time-course of drug concentrations will be plotted as appropriate.

  Cycle 1 (at least 28 days)

• Terminal half-life (t1/2)

  Terminal half-life (t1/2) will be summarized by cohort using descriptive statistics including number of study participants, mean, standard deviation, minimum, median, maximum, geometric mean, and coefficient of variation (CV) of the mean and geometric mean. Time-course of drug concentrations will be plotted as appropriate.

  Cycle 1 (at least 28 days)

• Volume of distribution

  Volume of distribution at various timepoints will be summarized by cohort using descriptive statistics including number of study participants, mean, standard deviation, minimum, median, maximum, geometric mean, and coefficient of variation (CV) of the mean and geometric mean. Time-course of drug concentrations will be plotted as appropriate.

  Cycle 1 (at least 28 days)

• Plasma clearance (CL)

  Plasma clearance (CL) will be summarized by cohort using descriptive statistics including number of study participants, mean, standard deviation, minimum, median, maximum, geometric mean, and coefficient of variation (CV) of the mean and geometric mean. Time-course of drug concentrations will be plotted as appropriate.

  Cycle 1 (at least 28 days)

• Recommended Phase 2 dose (RP2D) of tuspetinib

  The RP2D will be based on safety, efficacy, pharmacokinetic (PK), and pharmacodynamic (PD) considerations.

  4 years

Secondary Outcomes (10)

• Complete remission (CR)

  4 years

• Complete remission with partial hematologic recovery (CRh)

  4 years

• Complete remission with incomplete platelet recovery (CRp)

  4 years

• Complete remission with incomplete hematologic recovery (CRi)

  4 years

• Partial remission (PR)

  4 years

Other Outcomes (2)

• Percent inhibition of phosphorylation of targeted proteins

  4 years

• Mutation status of genes after treatment with tuspetinib

  4 years

Study Arms (5)

Part A Dose Escalation [COMPLETED]

EXPERIMENTAL

Part A dose escalation of tuspetinib as a single agent is planned for up to 6 dose levels. If a study participant in dose escalation 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 participants (\<1/6 DLT observed) in Part A, up to 20 evaluable participants can be enrolled in Part B at that dose level.

Drug: Tuspetinib

Part B Dose Exploration [ACTIVE, NOT RECRUITING]

EXPERIMENTAL

Part B dose exploration of tuspetinib as a single agent is planned for up to 4 dose levels.

Drug: Tuspetinib

Part C Dose Expansion (tuspetinib as a single agent) [COMPLETE]

EXPERIMENTAL

Part C dose expansion of tuspetinib as a single agent is planned for 2 dose levels. Study participants will be randomly assigned to either arm based on the number of slots available. The initial tuspetinib dose will be 120 mg.

Drug: Tuspetinib

Part C Dose Expansion (tuspetinib plus venetoclax) [COMPLETE]

EXPERIMENTAL

Part C dose expansion of tuspetinib in combination with venetoclax is planned for 2 dose levels. The initial tuspetinib dose will be 80 mg.

Drug: Tuspetinib; Drug: Venetoclax Oral Tablet

Part D Dose Exploration (tuspetinib plus venetoclax and azacitidine) [ACTIVE, RECRUITING - US Sites]

EXPERIMENTAL

Part D dose exploration of tuspetinib in combination with venetoclax and azacitidine is planned for up to 6 dose levels. The initial tuspetinib dose will be 40 mg.

Drug: Tuspetinib; Drug: Venetoclax Oral Tablet; Drug: Azacitidine for Intravenous Infusion

Interventions

Tuspetinib DRUG

Daily (QD), continuous dosing

Also known as: HM43239

Part A Dose Escalation [COMPLETED]; Part B Dose Exploration [ACTIVE, NOT RECRUITING]; Part C Dose Expansion (tuspetinib as a single agent) [COMPLETE]; Part C Dose Expansion (tuspetinib plus venetoclax) [COMPLETE]; Part D Dose Exploration (tuspetinib plus venetoclax and azacitidine) [ACTIVE, RECRUITING - US Sites]

Venetoclax Oral Tablet DRUG

Venetoclax will be given to study participants in the Part C tuspetinib plus venetoclax combination treatment group either in 50 mg or 100 mg tablets

Also known as: Venetoclax

Part C Dose Expansion (tuspetinib plus venetoclax) [COMPLETE]; Part D Dose Exploration (tuspetinib plus venetoclax and azacitidine) [ACTIVE, RECRUITING - US Sites]

Azacitidine for Intravenous Infusion DRUG

Azacitidine will be given to study participants in Part D as intravenous infusion at a dose of 75 mg/m\^2

Also known as: Azacitidine

Part D Dose Exploration (tuspetinib plus venetoclax and azacitidine) [ACTIVE, RECRUITING - US Sites]

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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:
• Refractory to at least 1 cycle of prior therapy
• 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.
• Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3× institutional upper limit normal (ULN)
• Total serum bilirubin ≤ 1.5× institutional ULN
• 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
• 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,

You may not qualify if:

• Study participant was diagnosed with acute promyelocytic leukemia (APL).
• Study participant has known BCR-ABL-positive leukemia.
• Study participant has an active malignancy other than AML, MDS-IB2, or CMML.
• Study participant has persistent non-hematological toxicities of ≥ Grade 2 (CTCAE v4.03), with symptoms and objective findings, from prior AML, MDS-IB2, or CMML treatment (including chemotherapy, kinase inhibitors, immunotherapy, experimental agents, radiation, or surgery)
• Study participant has had hematopoietic stem cell transplant (HSCT) and meets any of the following criteria:
• 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
• Had a donor lymphocyte infusion (DLI) ≤ 30 days prior to the first study dose.
• Study participant has meningeal or central nervous system (CNS) involvement with leukemia or other CNS disease related to underlying and secondary effects of malignancy.
• Study participant has disseminated intravascular coagulation abnormality (DIC).
• Study participant has had major surgery within 4 weeks prior to the first study dose.
• Study participant has had radiation therapy within 4 weeks prior to the first study dose.
• Study participant has congestive heart failure New York Heart Association (NYHA) class 3 or 4, or study participant 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%.
• Study participant has any of the following cardiac abnormalities of history:

Sponsors & Collaborators

• Aptose Biosciences Inc.: lead

Study Sites (34)

The Kirklin Clinic of UAB Hospital

Birmingham, Alabama, 35233, United States

RECRUITING

City of Hope Comprehensive Cancer Center

Duarte, California, 91010, United States

ACTIVE NOT RECRUITING

University of California Irvine

Irvine, California, 92697, United States

RECRUITING

UCSD Moores Cancer Center

La Jolla, California, 92093, United States

ACTIVE NOT RECRUITING

USC/Norris Comprehensive Cancer Center

Los Angeles, California, 90033, United States

RECRUITING

Stanford Cancer Center

Palo Alto, California, 94304, United States

RECRUITING

University of California, Davis

Sacramento, California, 95817, United States

RECRUITING

Yale University

New Haven, Connecticut, 06520, United States

RECRUITING

University of Miami - Miller School of Medicine

Miami, Florida, 33136, United States

RECRUITING

Emory University

Atlanta, Georgia, 30322, United States

ACTIVE NOT RECRUITING

Massachusetts General Hospital

Boston, Massachusetts, 02114, United States

ACTIVE NOT RECRUITING

Duke University Medical Center

Durham, North Carolina, 27705, United States

RECRUITING

Cleveland Clinic - Taussig Cancer Center

Cleveland, Ohio, 44106, United States

ACTIVE NOT RECRUITING

The Ohio State University Wexner Medical Center

Columbus, Ohio, 43210, United States

RECRUITING

MD Anderson Cancer Center

Huston, Texas, 77030, United States

RECRUITING

Border Medical Oncology

Albury, New South Wales, 2640, Australia

ACTIVE NOT RECRUITING

Royal Brisbane and Women's Hospital

Herston, Queensland, 4006, Australia

ACTIVE NOT RECRUITING

Townsville University Hospital

Townsville, Queensland, 4812, Australia

ACTIVE NOT RECRUITING

St Vincent's Hospital Melbourne

Fitzroy, Victoria, 3065, Australia

ACTIVE NOT RECRUITING

Sir Charles Gairdner Hospital

Nedlands, Western Australia, 6009, Australia

ACTIVE NOT RECRUITING

Universitätsklinikum Leipzig

Leipzig, Saxony, 04103, Germany

ACTIVE NOT RECRUITING

Charité Universitätsmedizin Berlin

Berlin, State of Berlin, 13353, Germany

ACTIVE NOT RECRUITING

Auckland City Hospital

Grafton, Auckland, 1023, New Zealand

ACTIVE NOT RECRUITING

Seoul National University Hospital

Seoul, Seoul, 03080, South Korea

COMPLETED

Asan Medical Center

Seoul, Seoul, 05505, South Korea

ACTIVE NOT RECRUITING

Samsung Medical Center

Seoul, Seoul, 06351, South Korea

ACTIVE NOT RECRUITING

Kyungpook National University Hospital

Daegu, 41944, South Korea

ACTIVE NOT RECRUITING

Pusan National University Hospital

Pusan, 49241, South Korea

ACTIVE NOT RECRUITING

Seoul National University Bundang Hospital

Seongnam, 13620, South Korea

ACTIVE NOT RECRUITING

Hospital Universitario Vall d'Hebron

Barcelona, Barcelona, 08035, Spain

ACTIVE NOT RECRUITING

Hospital Quirón Madrid

Pozuelo de Alarcón, Madrid, 28223, Spain

ACTIVE NOT RECRUITING

Hospital Universitario Central de Asturias

Oviedo, Principality of Asturias, 33011, Spain

ACTIVE NOT RECRUITING

Hospital Clinico Universitario de Valencia

Valencia, Valencia, 46010, Spain

ACTIVE NOT RECRUITING

Hospital Universitari i Politècnic La Fe

Valencia, Valencia, 46026, Spain

ACTIVE NOT RECRUITING

Related Publications (1)

• Sonowal H, Rice WG, Bejar R, Byun JY, Jung SH, Sinha R, Howell SB. Preclinical Development of Tuspetinib for the Treatment of Acute Myeloid Leukemia. Cancer Res Commun. 2025 Jan 1;5(1):74-83. doi: 10.1158/2767-9764.CRC-24-0258.

  PMID: 39665627 DERIVED

MeSH Terms

Conditions

Leukemia, Myeloid, Acute; Leukemia, Myelomonocytic, Chronic; Recurrence

Interventions

venetoclax; Azacitidine; Infusions, Intravenous

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Myelodysplastic-Myeloproliferative Diseases; Bone Marrow Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Aza Compounds; Organic Chemicals; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleosides; Administration, Intravenous; Drug Administration Routes; Drug Therapy; Therapeutics; Infusions, Parenteral

Study Officials

• Naval Daver, MD

  M.D. Anderson Cancer Center

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Rafael Bejar, MD, PhD

CONTACT

858-401-6852; rbejar@aptose.com

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: 1. Part A: Tuspetinib dose escalation 2. Part B: Tuspetinib dose exploration 3. Part C: Tuspetinib monotherapy dose expansion 4. Part C: Tuspetinib in combination with venetoclax ("doublet" therapy) dose expansion 5. Part D: Tuspetinib in combination with venetoclax and azacitidine ("triplet" therapy) dose exploration

Study Record Dates

• First Submitted: January 28, 2019
• First Posted: February 22, 2019
• Study Start: March 11, 2019
• Primary Completion (Estimated): November 1, 2026
• Study Completion (Estimated): April 1, 2027
• Last Updated: August 26, 2025

Record last verified: 2025-08

Locations

AU (5); NZ (1); KR (6); ES (5); US (15); DE (2)