Trial Review

Registering a new trial?

To achieve prospective registration, we recommend submitting your trial for registration at the same time as ethics submission.

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been endorsed by the ANZCTR. Before participating in a study, talk to your health care provider and refer to this information for consumers
Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT03850574




Registration number
NCT03850574
Ethics application status
Date submitted
28/01/2019
Date registered
22/02/2019
Date last updated
4/09/2024

Titles & IDs
Public title
Clinical Trial to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Tuspetinib (HM43239) in Patients With Relapsed or Refractory Acute Myeloid Leukemia
Scientific title
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)
Secondary ID [1] 0 0
2022-002826-29
Secondary ID [2] 0 0
HM-FLTI-101
Universal Trial Number (UTN)
Trial acronym
APTIVATE
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Leukemia, Myeloid, Acute 0 0
Refractory AML 0 0
Relapsed Adult AML 0 0
Myelodysplastic Syndrome With Excess Blasts-2 0 0
Chronic Myelomonocytic Leukemia 0 0
Condition category
Condition code
Cancer 0 0 0 0
Leukaemia - Acute leukaemia
Cancer 0 0 0 0
Leukaemia - Chronic leukaemia
Cancer 0 0 0 0
Children's - Leukaemia & Lymphoma
Blood 0 0 0 0
Haematological diseases
Blood 0 0 0 0
Other blood disorders
Blood 0 0 0 0
Anaemia

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Tuspetinib
Treatment: Drugs - Venetoclax Oral Tablet
Treatment: Drugs - Azacitidine for Intravenous Infusion

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.

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.

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.

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.

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.


Treatment: Drugs: Tuspetinib
Daily (QD), continuous dosing

Treatment: Drugs: Venetoclax Oral Tablet
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

Treatment: Drugs: Azacitidine for Intravenous Infusion
Azacitidine will be given to study participants in Part D as intravenous infusion at a dose of 75 mg/m\^2
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Frequency and severity of drug-related adverse events
Timepoint [1] 0 0
4 years
Primary outcome [2] 0 0
Maximum tolerated dose (MTD) of tuspetinib
Timepoint [2] 0 0
4 years
Primary outcome [3] 0 0
Maximum plasma concentration (Cmax)
Timepoint [3] 0 0
Cycle 1 (at least 28 days)
Primary outcome [4] 0 0
Minimum plasma concentration (Cmin)
Timepoint [4] 0 0
Cycle 1 (at least 28 days)
Primary outcome [5] 0 0
Area under the plasma concentration-time curve (AUC)
Timepoint [5] 0 0
Cycle 1 (at least 28 days)
Primary outcome [6] 0 0
Time to maximum concentration (Tmax)
Timepoint [6] 0 0
Cycle 1 (at least 28 days)
Primary outcome [7] 0 0
Terminal half-life (t1/2)
Timepoint [7] 0 0
Cycle 1 (at least 28 days)
Primary outcome [8] 0 0
Volume of distribution
Timepoint [8] 0 0
Cycle 1 (at least 28 days)
Primary outcome [9] 0 0
Plasma clearance (CL)
Timepoint [9] 0 0
Cycle 1 (at least 28 days)
Primary outcome [10] 0 0
Recommended Phase 2 dose (RP2D) of tuspetinib
Timepoint [10] 0 0
4 years
Secondary outcome [1] 0 0
Complete remission (CR)
Timepoint [1] 0 0
4 years
Secondary outcome [2] 0 0
Complete remission with partial hematologic recovery (CRh)
Timepoint [2] 0 0
4 years
Secondary outcome [3] 0 0
Complete remission with incomplete platelet recovery (CRp)
Timepoint [3] 0 0
4 years
Secondary outcome [4] 0 0
Complete remission with incomplete hematologic recovery (CRi)
Timepoint [4] 0 0
4 years
Secondary outcome [5] 0 0
Partial remission (PR)
Timepoint [5] 0 0
4 years
Secondary outcome [6] 0 0
Overall response rate
Timepoint [6] 0 0
4 years
Secondary outcome [7] 0 0
Duration of response
Timepoint [7] 0 0
4 years
Secondary outcome [8] 0 0
Disease-free survival (DFS)
Timepoint [8] 0 0
4 years
Secondary outcome [9] 0 0
Overall survival (OS)
Timepoint [9] 0 0
4 years
Secondary outcome [10] 0 0
Event-free survival (EFS)
Timepoint [10] 0 0
4 years

Eligibility
Key inclusion 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.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
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.)

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Other
Other design features
Phase
Phase 1
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
11/03/2019
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
1/12/2026
Actual
Sample size
Target
260
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD,VIC,WA
Recruitment hospital [1] 0 0
Border Medical Oncology - Albury
Recruitment hospital [2] 0 0
Royal Brisbane and Women's Hospital - Herston
Recruitment hospital [3] 0 0
Townsville University Hospital - Townsville
Recruitment hospital [4] 0 0
St Vincent's Hospital Melbourne - Fitzroy
Recruitment hospital [5] 0 0
Sir Charles Gairdner Hospital - Nedlands
Recruitment postcode(s) [1] 0 0
2640 - Albury
Recruitment postcode(s) [2] 0 0
4006 - Herston
Recruitment postcode(s) [3] 0 0
4812 - Townsville
Recruitment postcode(s) [4] 0 0
3065 - Fitzroy
Recruitment postcode(s) [5] 0 0
6009 - Nedlands
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
Alabama
Country [2] 0 0
United States of America
State/province [2] 0 0
California
Country [3] 0 0
United States of America
State/province [3] 0 0
Connecticut
Country [4] 0 0
United States of America
State/province [4] 0 0
Florida
Country [5] 0 0
United States of America
State/province [5] 0 0
Georgia
Country [6] 0 0
United States of America
State/province [6] 0 0
Massachusetts
Country [7] 0 0
United States of America
State/province [7] 0 0
North Carolina
Country [8] 0 0
United States of America
State/province [8] 0 0
Ohio
Country [9] 0 0
United States of America
State/province [9] 0 0
Texas
Country [10] 0 0
Germany
State/province [10] 0 0
Saxony
Country [11] 0 0
Germany
State/province [11] 0 0
Berlin
Country [12] 0 0
Korea, Republic of
State/province [12] 0 0
Daegu
Country [13] 0 0
Korea, Republic of
State/province [13] 0 0
Pusan
Country [14] 0 0
Korea, Republic of
State/province [14] 0 0
Seongnam
Country [15] 0 0
Korea, Republic of
State/province [15] 0 0
Seoul
Country [16] 0 0
New Zealand
State/province [16] 0 0
Auckland
Country [17] 0 0
Spain
State/province [17] 0 0
Asturias
Country [18] 0 0
Spain
State/province [18] 0 0
Madrid
Country [19] 0 0
Spain
State/province [19] 0 0
Barcelona
Country [20] 0 0
Spain
State/province [20] 0 0
Valencia

Funding & Sponsors
Primary sponsor type
Commercial sector/industry
Name
Aptose Biosciences Inc.
Address
Country

Ethics approval
Ethics application status

Summary
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.
Trial website
https://clinicaltrials.gov/study/NCT03850574
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Naval Daver, MD
Address 0 0
M.D. Anderson Cancer Center
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Rafael Bejar, MD, PhD
Address 0 0
Country 0 0
Phone 0 0
858-401-6852
Fax 0 0
Email 0 0
[email protected]
Contact person for scientific queries



Summary Results

For IPD and results data, please see https://clinicaltrials.gov/study/NCT03850574