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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/ct2/show/NCT03850574




Registration number
NCT03850574
Ethics application status
Date submitted
28/01/2019
Date registered
22/02/2019
Date last updated
7/12/2023

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
HM-FLTI-101
Universal Trial Number (UTN)
Trial acronym
APTIVATE
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Relapsed or Refractory Acute Myeloid 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

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

Experimental: Part A Dose Escalation - For Part A (tuspetinib as a single agent), dose escalation cohort is planned up to 6 dose levels. If a subject in the dose escalation cohort 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 patients (<1/6 DLT observed) in Part A, up to 20 evaluable patients can be enrolled in Part B at that dose level.

Experimental: Part B Dose Exploration - For Part B (tuspetinib as a single agent), dose exploration cohort is planned up to 4 dose levels.

Experimental: Part C Dose Expansion (tuspetinib as a single agent) - Part C, dose expansion, consists of 2 arms (tuspetinib as a single agent or tuspetinib plus venetoclax). Patients will be randomly assigned to either arm based on the number of slots available. The initial tuspetinib dose for the single arm will be 120mg.

Experimental: Part C Dose Expansion (Combination Arm - tuspetinib and venetoclax) - Part C, dose expansion, consists of 2 arms (tuspetinib or tuspetinib plus venetoclax). Patients will be randomly assigned to either arm based on the number of slots available. The initial tuspetinib dose for the combo arm will be 80mg.


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

Treatment: Drugs: Venetoclax Oral Tablet
Venetoclax will be given to patients in combo treatment group (Part C) either in 50 mg or 100 mg tablets
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Recommended Phase 2 dose
Timepoint [1] 0 0
4 years
Primary outcome [2] 0 0
Safety of HM43239
Timepoint [2] 0 0
4 years
Primary outcome [3] 0 0
Tolerability of HM43239
Timepoint [3] 0 0
4 years
Primary outcome [4] 0 0
Safety of HM43239 in combination with venetoclax
Timepoint [4] 0 0
4 years
Primary outcome [5] 0 0
Tolerability of HM43239 in combination with venetoclax
Timepoint [5] 0 0
4 years
Secondary outcome [1] 0 0
Anti-leukemic activity of HM43239
Timepoint [1] 0 0
4 years
Secondary outcome [2] 0 0
Anti-leukemic activity of HM43239 in combination with venetoclax
Timepoint [2] 0 0
4 years
Secondary outcome [3] 0 0
Pharmacokinetic variables including maximum plasma concentration (Cmax)
Timepoint [3] 0 0
Cycle 1 (at least 28 days)
Secondary outcome [4] 0 0
Pharmacokinetic variables including minimum plasma concentration (Cmin)
Timepoint [4] 0 0
Cycle 1 (at least 28 days)
Secondary outcome [5] 0 0
Pharmacokinetic variables including area under the curve (AUC)
Timepoint [5] 0 0
Cycle 1 (at least 28 days)
Secondary outcome [6] 0 0
Pharmacokinetic variables including volume of distribution
Timepoint [6] 0 0
Cycle 1 (at least 28 days)
Secondary outcome [7] 0 0
Pharmacokinetic variables including clearance
Timepoint [7] 0 0
Cycle 1 (at least 28 days)
Secondary outcome [8] 0 0
Pharmacodynamic variables
Timepoint [8] 0 0
4 years

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

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled 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/Phase 2
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
1/08/2024
Actual
Sample size
Target
218
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
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)
Trial website
https://clinicaltrials.gov/ct2/show/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/ct2/show/NCT03850574