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

PHASE1PHASE2RECRUITING

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.

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Study details:

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).

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Eligibility criteria

Researchers look for people who fit a certain description, called eligibility criteria. See if you qualify.

Inclusion criteria

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

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.

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Eligibility

Age eligible for study : 18 and older

Healthy volunteers accepted : No

Gender eligible for study: All

Things to know

Study dates

Study start: 2019-03-11

Primary completion: 2026-11-01

Study completion finish: 2027-04-01

Study type

TREATMENT

Phase

PHASE1

PHASE2

Trial ID

NCT03850574

Intervention or treatment

DRUG: Tuspetinib

DRUG: Venetoclax Oral Tablet

DRUG: Azacitidine for Intravenous Infusion

Conditions

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

Image related to Leukemia, Myeloid, Acute

Condition: Leukemia, Myeloid, Acute, Refractory AML and more
DRUG: Tuspetinib and other drugs
Nedlands, Western Australia, Australia and more
Sponsor: Aptose Biosciences Inc.

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Find a site

Closest Location:

Sir Charles Gairdner Hospital

Research sites nearby

Select from list below to view details:

Sir Charles Gairdner Hospital
Nedlands, Western Australia, Australia
Border Medical Oncology
Albury, New South Wales, Australia
Royal Brisbane and Women's Hospital
Herston, Queensland, Australia
Townsville University Hospital
Townsville, Queensland, Australia

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Participant Group/Arm	Intervention/Treatment
EXPERIMENTAL: Part A Dose Escalation [COMPLETED] 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 Daily (QD), continuous dosing
EXPERIMENTAL: Part B Dose Exploration [ACTIVE, NOT RECRUITING] Part B dose exploration of tuspetinib as a single agent is planned for up to 4 dose levels.	DRUG: Tuspetinib Daily (QD), continuous dosing
EXPERIMENTAL: Part C Dose Expansion (tuspetinib as a single agent) [ACTIVE, NOT RECRUITING] 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 Daily (QD), continuous dosing
EXPERIMENTAL: Part C Dose Expansion (tuspetinib plus venetoclax) [ACTIVE, NOT RECRUITING] 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 Daily (QD), continuous dosing
EXPERIMENTAL: Part D Dose Exploration (tuspetinib plus venetoclax and azacitidine) [ACTIVE, NOT RECRUITING] 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 Daily (QD), continuous dosing

What is the study measuring?

Primary outcome

Primary Outcome Measure	Primary Outcome Description	Primary Outcome Time Frame
Frequency and severity of drug-related adverse events	Not Specified	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 outcome

Secondary Outcome Measure	Secondary Outcome Description	Secondary Outcome Time Frame
Complete remission (CR)	Complete remission (CR) will be summarized using descriptive statistics.	4 years
Complete remission with partial hematologic recovery (CRh)	Complete remission with partial hematologic recovery (CRh) will be summarized using descriptive statistics.	4 years
Complete remission with incomplete platelet recovery (CRp)	Complete remission with incomplete platelet recovery (CRp) will be summarized using descriptive statistics.	4 years
Complete remission with incomplete hematologic recovery (CRi)	Complete remission with incomplete hematologic recovery (CRi) will be summarized using descriptive statistics.	4 years
Partial remission (PR)	Partial remission (PR) will be summarized using descriptive statistics.	4 years
Overall response rate	Overall response rate will be summarized using descriptive statistics.	4 years
Duration of response	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.	4 years
Disease-free survival (DFS)	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.	4 years
Overall survival (OS)	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.	4 years
Event-free survival (EFS)	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.	4 years

Frequently Asked Questions

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References

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