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

Phase 1

Recruiting

• Conditions: Leukemia, Myeloid, Acute; Refractory AML; Relapsed Adult AML; Myelodysplastic Syndrome with Excess Blasts-2; Chronic Myelomonocytic Leukemia
• Interventions: Drug: Tuspetinib; Drug: Venetoclax Oral Tablet; Drug: Azacitidine for Intravenous Infusion

• Registration Number: NCT03850574
• Lead Sponsor: Aptose Biosciences Inc.

Brief 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)

Detailed Description

This is a Phase 1/2, open-label, multi-center study designed to assess the efficacy, safety, tolerability, and pharmacokinetics, including determining the recommended Phase 2 dose (RP2D) of tuspetinib (HM43239) in subjects with relapsed or treatment-refractory acute myeloid leukemia (AML).

Part C: This portion of the study will evaluate tuspetinib (HM43239) as monotherapy in patients with relapsed or refractory (R/R) AML, focusing on safety, tolerability, pharmacokinetics, and preliminary efficacy (Aptivate).

Part D: This portion of the study will evaluate the safety, tolerability, and PK parameters of tuspetinib (HM43239) in combination with venetoclax and azacitidine when administered to newly diagnosed AML patients who are ineligible for induction chemotherapy (Tuscany).

Study Timeline

• Study First Submitted: 2019-01-28
• Study First Submitted QC: 2019-02-20
• Study First Posted: 2019-02-22
• Study Start: 2019-03-11
• Status Verified: 2024-12
• Last Update Submitted: 2024-12-18
• Last Update Posted: 2024-12-20
• Primary Completion: 2026-11
• Study Completion: 2027-04

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 240

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

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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.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Part A Dose Escalation [COMPLETED]	Tuspetinib	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.
Part B Dose Exploration [ACTIVE, NOT RECRUITING]	Tuspetinib	Part B dose exploration of tuspetinib as a single agent is planned for up to 4 dose levels.
Part C Dose Expansion (tuspetinib plus venetoclax) [COMPLETE]	Venetoclax Oral Tablet	Part C dose expansion of tuspetinib in combination with venetoclax is planned for 2 dose levels. The initial tuspetinib dose will be 80 mg.
Part D Dose Exploration (tuspetinib plus venetoclax and azacitidine) [ACTIVE, RECRUITING - US Sites]	Venetoclax Oral Tablet	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.
Part D Dose Exploration (tuspetinib plus venetoclax and azacitidine) [ACTIVE, RECRUITING - US Sites]	Azacitidine for Intravenous Infusion	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.
Part D Dose Exploration (tuspetinib plus venetoclax and azacitidine) [ACTIVE, RECRUITING - US Sites]	Tuspetinib	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.
Part C Dose Expansion (tuspetinib as a single agent) [COMPLETE]	Tuspetinib	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.
Part C Dose Expansion (tuspetinib plus venetoclax) [COMPLETE]	Tuspetinib	Part C dose expansion of tuspetinib in combination with venetoclax is planned for 2 dose levels. The initial tuspetinib dose will be 80 mg.

Primary Outcome Measures

Name	Time	Method
Frequency and severity of drug-related adverse events	4 years
Maximum tolerated dose (MTD) of tuspetinib	4 years	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.
Maximum plasma concentration (Cmax)	Cycle 1 (at least 28 days)	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.
Minimum plasma concentration (Cmin)	Cycle 1 (at least 28 days)	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.
Area under the plasma concentration-time curve (AUC)	Cycle 1 (at least 28 days)	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.
Time to maximum concentration (Tmax)	Cycle 1 (at least 28 days)	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.
Terminal half-life (t1/2)	Cycle 1 (at least 28 days)	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.
Volume of distribution	Cycle 1 (at least 28 days)	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.
Plasma clearance (CL)	Cycle 1 (at least 28 days)	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.
Recommended Phase 2 dose (RP2D) of tuspetinib	4 years	The RP2D will be based on safety, efficacy, pharmacokinetic (PK), and pharmacodynamic (PD) considerations.

Secondary Outcome Measures

Name	Time	Method
Complete remission (CR)	4 years	Complete remission (CR) will be summarized using descriptive statistics.
Complete remission with partial hematologic recovery (CRh)	4 years	Complete remission with partial hematologic recovery (CRh) will be summarized using descriptive statistics.
Complete remission with incomplete platelet recovery (CRp)	4 years	Complete remission with incomplete platelet recovery (CRp) will be summarized using descriptive statistics.
Complete remission with incomplete hematologic recovery (CRi)	4 years	Complete remission with incomplete hematologic recovery (CRi) will be summarized using descriptive statistics.
Partial remission (PR)	4 years	Partial remission (PR) will be summarized using descriptive statistics.
Overall response rate	4 years	Overall response rate will be summarized using descriptive statistics.
Duration of response	4 years	Survival curves and median for time-to-event variables will be estimated using the Kaplan-Meier method and will be reported along with corresponding 95% confidence intervals.
Disease-free survival (DFS)	4 years	Survival curves and median for time-to-event variables will be estimated using the Kaplan-Meier method and will be reported along with corresponding 95% confidence intervals.
Overall survival (OS)	4 years	Survival curves and median for time-to-event variables will be estimated using the Kaplan-Meier method and will be reported along with corresponding 95% confidence intervals.
Event-free survival (EFS)	4 years	Survival curves and median for time-to-event variables will be estimated using the Kaplan-Meier method and will be reported along with corresponding 95% confidence intervals.

Trial Locations

Locations (34)

The Kirklin Clinic of UAB Hospital; 🇺🇸 Birmingham, Alabama, United States

City of Hope Comprehensive Cancer Center; 🇺🇸 Duarte, California, 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

Stanford Cancer Center; 🇺🇸 Palo Alto, California, United States

University of California, Davis; 🇺🇸 Sacramento, California, United States

Yale University; 🇺🇸 New Haven, Connecticut, United States

University of Miami - Miller School of Medicine; 🇺🇸 Miami, Florida, United States

Emory University; 🇺🇸 Atlanta, Georgia, United States

Massachusetts General Hospital; 🇺🇸 Boston, Massachusetts, United States

Duke University Medical Center; 🇺🇸 Durham, North Carolina, United States

Cleveland Clinic - Taussig Cancer Center; 🇺🇸 Cleveland, Ohio, United States

The Ohio State University Wexner Medical Center; 🇺🇸 Columbus, Ohio, United States

MD Anderson Cancer Center; 🇺🇸 Huston, Texas, United States

Border Medical Oncology; 🇦🇺 Albury, New South Wales, Australia

Royal Brisbane and Women's Hospital; 🇦🇺 Herston, Queensland, Australia

Townsville University Hospital; 🇦🇺 Townsville, Queensland, Australia

St Vincent's Hospital Melbourne; 🇦🇺 Fitzroy, Victoria, Australia

Sir Charles Gairdner Hospital; 🇦🇺 Nedlands, Western Australia, Australia

Universitätsklinikum Leipzig; 🇩🇪 Leipzig, Saxony, Germany

Charité Universitätsmedizin Berlin; 🇩🇪 Berlin, Germany

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

Seoul National University Hospital; 🇰🇷 Seoul, Korea, Republic of

Asan Medical Center; 🇰🇷 Seoul, Korea, Republic of

Samsung Medical Center; 🇰🇷 Seoul, Korea, Republic of

Auckland City Hospital; 🇳🇿 Grafton, Auckland, New Zealand

Hospital Universitario Central de Asturias; 🇪🇸 Oviedo, Asturias, Spain

Hospital Quirón Madrid; 🇪🇸 Pozuelo De Alarcón, Madrid, Spain

Hospital Universitario Vall d'Hebron; 🇪🇸 Barcelona, Spain

Hospital Clinico Universitario de Valencia; 🇪🇸 Valencia, Spain

Hospital Universitari i Politècnic La Fe; 🇪🇸 Valencia, Spain