Evaluating the safety and effectiveness of tuspetinib in patients with relapsed or refractory acute myeloid leukemia

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)

This study is testing a new drug called tuspetinib to see if it can safely help people with relapsed or hard-to-treat types of leukemia and related blood disorders.

Quick facts

• Phase: Phase1; Phase2
• Study type: Interventional
• Enrollment: 240 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: Aptose Biosciences Inc. (Industry-sponsored)
• Drugs / interventions: CAR-T, chemotherapy, immunotherapy, radiation, tuspetinib
• Locations: 34 sites (Birmingham, Alabama and 33 other locations)
• Trial ID: NCT03850574 on ClinicalTrials.gov

What this trial studies

This clinical trial aims to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of tuspetinib (HM43239) in patients diagnosed with relapsed or refractory acute myeloid leukemia (AML), myelodysplastic syndromes with increased blasts grade 2 (MDS-IB2), or chronic myelomonocytic leukemia (CMML). The study will be conducted in multiple phases, where tuspetinib will be administered either as a single agent or in combination with other drugs like venetoclax and azacitidine. The trial will determine the recommended Phase 2 dose and evaluate preliminary efficacy in these patient populations.

Who should consider this trial

Good fit: Ideal candidates include adults with relapsed or refractory acute myeloid leukemia, myelodysplastic syndromes with increased blasts, or chronic myelomonocytic leukemia who have undergone at least one prior therapy.

Not a fit: Patients who are newly diagnosed with acute myeloid leukemia and are eligible for standard induction chemotherapy may not benefit from this study.

Why it matters

Potential benefit: If successful, this trial could provide a new treatment option for patients with difficult-to-treat forms of acute myeloid leukemia.

How similar studies have performed: Other studies have shown promise with similar approaches in treating relapsed or refractory acute myeloid leukemia, indicating potential for success.

Eligibility criteria

Inclusion Criteria for Parts A/B/C:

* 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:

  1. Refractory to at least 1 cycle of prior therapy
  2. 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.

  1. Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3× institutional upper limit normal (ULN)
  2. Total serum bilirubin ≤ 1.5× institutional ULN
  3. 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

  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 an acceptable highly effective method of birth control starting at screening and throughout the study period and for 90 days after the final study drug administration.
* Female study participants must not be breastfeeding at screening and during the study period, and for 90 days after the final study drug administration
* Female study participants must not donate ova starting at screening and throughout the study period, and for 90 days after the final study drug administration.
* Male study participants 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 study participants must not donate sperm starting at screening and throughout the study period and for 90 days after the final study drug administration.
* Study participant agrees not to participate in another interventional study while on treatment.

Exclusion Criteria for Parts A/B/C:

Study participants must not enter the study if any of the following exclusion criteria are met:

* 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:

  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. 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:

  1. Study participant 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. Study participant has a mean QT interval (QTc) by Friderica's method (QTcF) \> 450 ms in three successive screening measurements.
  3. Study participant 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.
* Study participant is known to have active infection including any identified active COVID-19 infection.
* Study participant is known to have human immunodeficiency virus infection.
* Study participant has known active hepatitis B or C, or other active hepatic disorder.
* Study participant has any condition which, in the Investigator's opinion, makes the study participant unsuitable for study participation.
* Study participant has a history of Grade 3 or 4 non-hematologic toxicity related to tyrosine kinase inhibitor.

Inclusion Criteria for Part D:

* Study participant is defined as having morphologically documented newly diagnosed previously untreated primary or secondary AML by the World Health Organization (WHO) criteria (2016) and considered ineligible to receive intensive chemotherapy.

Study participants ≥ 75 years of age are considered ineligible to receive intensive chemotherapy if they meet any of the following criteria:

1. ECOG Performance Status of 2 or 3;
2. Cardiac history of congestive heart failure (CHF) requiring treatment or ejection fraction ≤ 50% or chronic stable angina;
3. Diffusing capacity of the lung for carbon monoxide (DLCO) ≤ 65% or forced expiratory volume during the first second (FEV1) ≤ 65%;
4. Creatinine clearance ≥ 30 mL/min to \< 45 ml/min;
5. Moderate hepatic impairment with total bilirubin \> 1.5 to ≤ 3.0×ULN;
6. Any other comorbidity that the Investigator judges to be incompatible with intensive chemotherapy must be reviewed and approved by the Medical Monitor during screening and prior to treatment.

Study participants are considered ineligible to receive intensive chemotherapy based on their age being ≥ 75 years.

* Study participant \< 75 years has an ECOG performance status ≤ 2; study participant ≥ 75 years has an ECOG performance status 0-2.
* Study participant must meet the following criteria as indicated on the clinical laboratory tests:

  1. Serum AST and ALT ≤ 3× institutional ULN unless considered due to leukemic organ involvement.
  2. Total serum bilirubin ≤ 3x institutional ULN unless considered due to leukemic organ involvement for study participants \< 75 years; total serum bilirubin ≤ 1.5x institutional ULN (or ≤ 3x institutional ULN if documented history of Gilbert's syndrome) unless considered due to leukemic organ involvement for study participants ≥ 75 years.
  3. Creatinine clearance as calculated by the Cockcroft-Gault formula or measured by 24-h urine collection of ≥ 30 mL/min for study participants \< 75 years; creatinine clearance as calculated by the Cockcroft-Gault formula or measured by 24-h urine collection of ≥ 45 mL/min for study participants ≥ 75 years.
* 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

  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 an acceptable highly effective contraception starting at screening and throughout the study period and for 90 days after the final study drug administration.
* Female study participants must not be breastfeeding at screening and during the study period, and for 90 days after the final study drug administration.
* Female study participants must not donate ova starting at screening and throughout the study period, and for 90 days after the final study drug administration.
* Male study participants 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 study participants must not donate sperm starting at screening and throughout the study period and for 90 days after the final study drug administration.
* Study participant agrees not to participate in another interventional study while on treatment.

Exclusion Criteria for Part D:

Study participants must not enter the study if any of the following exclusion criteria are met:

* 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.
* Study participant has received treatment with the following:

  1. An HMA, VEN (or other BCL-2 inhibitor), a tyrosine kinase inhibitor (TKI), a FLT3 inhibitor (FLT3i), a hematopoietic stem cell transplant (HSCT), and/or a chemotherapeutic agent for antecedent myeloid neoplasm (Note: Prior chemotherapy for solid tumors considered in remission is allowed.)
  2. CAR-T cell therapy
  3. Experimental therapies for antecedent myeloid neoplasms
  4. Current participation in another research or observational study
* Study participant has persistent non-hematological toxicities of ≥ Grade 2 (CTCAE v4.03), with symptoms and objective findings, from treatment for antecedent myeloid neoplasms (including chemotherapy, kinase inhibitors, immunotherapy, experimental agents, immunosuppressive therapy, radiation, or surgery).
* 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:

  1. Study participant 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. Study participant has a mean QT interval (QTc) by Friderica's method (QTcF) \> 450 ms in three successive screening measurements.
  3. Study participant 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.
* Study participant is known to have active infection, including any identified active COVID-19 infection.
* Study participant is known to have human immunodeficiency virus infection.
* Study participant has known active hepatitis B or C, or other active hepatic disorder.
* Study participant has any condition which, in the Investigator's opinion, makes the study participant unsuitable for study participation, including a chronic respiratory disease that requires continuous oxygen, or a significant history of renal, neurologic, psychiatric, endocrinologic, metabolic, immunologic, hepatic, or cardiovascular disease, or any other medical condition or known hypersensitivity to any of the study medications including excipients of VEN and AZA that in the opinion of the Investigator would adversely affect participating in this study.
* Study participant exhibits evidence of other clinically significant uncontrolled systemic infection requiring therapy (viral, bacterial, or fungal) or other medical conditions (e.g., infection, heart failure, COPD flare, etc.).
* Study participant has a white blood cell count \> 25 × 10\^9/L. (Treatment with hydroxyurea or use of leukapheresis are permitted to meet this criterion.)

Where this trial is running

Birmingham, Alabama and 33 other locations

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

Study contacts

• Principal investigator: Naval Daver, MD — M.D. Anderson Cancer Center
• Study coordinator: Rafael Bejar, MD, PhD

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