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Trial registered on ANZCTR


Registration number
ACTRN12621001713886
Ethics application status
Approved
Date submitted
30/09/2021
Date registered
15/12/2021
Date last updated
21/07/2024
Date data sharing statement initially provided
15/12/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
A dose determining trial to assess the recommended dose of ES-3000 and ASTX727 for patients with Myelodysplasia
Scientific title
MDS05/D1: (MYDAS-T) Assessing the safety of ES-3000 and ASTX727 in patients with myelodysplasia
Secondary ID [1] 305133 0
None
Universal Trial Number (UTN)
Trial acronym
MYDAS-T Run ES IN
Linked study record
This is a component(Domain 1) study associated with master protocol registered as ACTRN12622000410752

Health condition
Health condition(s) or problem(s) studied:
Myelodysplasia 323371 0
Condition category
Condition code
Cancer 320942 320942 0 0
Leukaemia - Acute leukaemia

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
There are 2 drugs used in this treatment domain of the platform trial; ES-3000 and ASTX727. This domain is separated into 2 parts; Part 1 is dose finding and part 2 is expanding recruitment using the recommended phase 2 dose (RP2D).

The first cycle of the protocol treatment will include only ES-3000 (without ASTX727) to establish safety and and recommended part 2 dose of the combination.

Cycle 2 onwards will be a combination of ES-3000 and standard dose of ASTX727, to identify the maximum tolerated dose (MTD) and recommended phase 2 dose of ES-3000 in combination with ASTX727. The standard dose of AST727 is 1 tablet (35 mg decitabine and 100 mg cedazuridine).

In the part 1 dose finding run in study, ES-3000 (tablet) will be administered orally 3 times per day approximately every 8 hours on Days 1 to 14 of each 28-day cycle with the starting dose of 60mg TiD. Doses will increase or decrease by 20mg each dose level, depending on the findings of the safety review. Safety review by assessing adverse events will be assessed at the end of the treatment cycle. Depending on the results of the safety review, the dose may increase or decrease.

From cycle 2 and onwards, subjects will receive oral ASTX727 (tablet) on days 1 to 5 of each cycle. Patients will continue treatment until reaching a defined event; unacceptable toxicity, disease progression.

Drug accountability will be performed by the administering institutions to assess compliance.
Intervention code [1] 321542 0
Treatment: Drugs
Comparator / control treatment
There is no comparator arm
Control group
Uncontrolled

Outcomes
Primary outcome [1] 328724 0
To assess the occurrence of dose limiting toxicities of ES-3000 to provide a recommended phase 2 dose. This will be completed by reviewing the patients blood biochemistry markers, peripheral blood counts for adverse events.
Timepoint [1] 328724 0
After day 28 cycle 1 and cycle 2 have been completed for each dose cohort
Primary outcome [2] 329520 0
To assess the incidence and severity of adverse events of ES-3000 and ASTX727. This will be completed by reviewing patients blood biochemistry markers, cell counts (peripheral blood and bone marrow) and physical exam.
Timepoint [2] 329520 0
After all patients have completed day 28 cycle 2
Primary outcome [3] 329521 0
To assess the overall response rates in the dose expansion phase of the trial.. This will be assessed using blood and bone marrow markers.
Timepoint [3] 329521 0
After 3 and 6 months of treatment
Secondary outcome [1] 400128 0
Efficacy of treatment combination using response assessment will be assessed. This will be assessed using blood and bone marrow markers.
Timepoint [1] 400128 0
At 6months of treament, at the end of treatment and after 5 years of follow up for all patients.
Secondary outcome [2] 400129 0
Event Free survival will be calculated using blood and bone markers indicating response.
Timepoint [2] 400129 0
At 6months of treatment, at the end of treatment, and when all patients have completed 5 years of follow up.
Secondary outcome [3] 402854 0
Overall survival will be calculated for all patients utilising the date the patient passed away. This will be sourced from medical records.
Timepoint [3] 402854 0
Rates will be assessed after 6m of treatment, at the end of treatment and after 5 years of follow up for all patients.
Secondary outcome [4] 402856 0
The time to response will be calculated. Response will be informed by blood and bone markers.
Timepoint [4] 402856 0
This will be calculated after 6m of treatment, at the end of all treatment and after 5 yrs of follow up.
Secondary outcome [5] 402860 0
The time to transfusion independence will be assessed. This will be sourced by the number of transfusions given to the patient.
Timepoint [5] 402860 0
This will be assessed after 6m of treatment and at the end of treatment.
Secondary outcome [6] 402864 0
Quality of Life will be assed together as a composite outcome using the EQ5D and EORTC QLQ 30 tools
Timepoint [6] 402864 0
This will be analysed at the end of treatment and after 5 years of follow up
Secondary outcome [7] 402865 0
Frailty will be assessed as a composite outcome using the Instrumental Activities of Daily Living Scale, Timed up and go and the Standardised Mini-Mental State Examination.
Timepoint [7] 402865 0
These will be analysed at the end of treatment and after 5 years of follow up.

Eligibility
Key inclusion criteria
Eligibility criteria are noted in the MDS05 Master Protocol as below:
1. Provision of written informed consent
2. Provision of written informed consent to the ALLG NBCR
3. Age 18+ (Age 16-17 permitted if consent for minor PICF approved by the authorising HREC)
4. A diagnosis of MDS or AML with < 30% blasts
5. Any other inclusion criteria mentioned in the study domain e.g., older AML patients (> 30% blasts) who are not suitable for intensive arms of AML trials or treatment may be suitable for certain domains of the MDS trials. This will be specified in the domain inclusion criteria.

The following point must also be met to be eligible for participation in this domain:
1. All previously treatment naïve myelodysplasia patients with IPSS score >= 1.5 and be eligible for standard AZA treatment in Australia. AML with blasts <30% (in peripheral blood and bone marrow) will also be eligible for this study.
Minimum age
16 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Exclusion criteria as in the Master protocol will apply as below:
1. History of other malignancy requiring active systemic treatment, or which is likely to result in an expected survival time of < 12 months.
2. Viral infection with known HIV or viral hepatitis type B or C not adequately controlled by antiviral medication.
3. Prior bone marrow or stem cell transplantation for a diagnosis of Myelodysplasia or acute myeloid leukaemia. If stem cell transplantation has been undertaken for other reasons- refer to individual domain and discuss with study team.

In addition, the following patients will be excluded:
1. Patients with QTcF> 480msecs (females) and QTcF> 450msecs (males) will be excluded from this study
2. Subjects who has received allogeneic HSCT or solid organ transplantation.
3. Subject has a history of an active malignancy within the past 2 years prior to study entry, with the exception of:
a. Adequately treated in situ carcinoma of the cervix uteri
b. Adequately treated basal cell carcinoma or localized squamous cell carcinoma
of the skin
c. Asymptomatic prostate cancer without known metastatic disease and with no
requirement for therapy
4. Subject has a known positive test for human immunodeficiency virus (HIV). Note: HIV testing is not required at Screening.
5. Subject has chronic active hepatitis B (HBV) or hepatitis C (HCV) requiring treatment.
6. Subject exhibits evidence of other clinically significant uncontrolled condition(s) including, but not limited to ongoing systemic infection (viral, bacterial, or fungal).
7. Subject has a malabsorption syndrome or other condition that precludes an enteral route of administration.
8. Subject has history of a significant cardiovascular, endocrine, hepatic, immunologic metabolic, neurologic, psychiatric, pulmonary, renal disease, or any other condition that in the opinion of the investigator would adversely affect his/her participation in this study or interpretation of study results. Note: For subjects who have required an intervention for any above diseases within the past 6 months requires a discussion between the investigator and study team.
9. Subject is concurrently participating in another therapeutic clinical trial.
10. Subject is pregnant or breastfeeding.

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
Single group
Other design features
Phase
Phase 1 / Phase 2
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
This open-label, Phase 1b dose-escalation study evaluates the safety and tolerability of ES-3000 in combination with ASTX727 in subjects with MDS. The initial dose determining part of the trial will be followed by an expansion safety cohort. The dose escalation portion will enrol approximately up to 20 patients in the dose determining phase. The design will start with a dose of ES-3000 at 60mg TID in combination with standard dose of ASTX727. Dose Limiting Toxicities (DLTs) will be assessed during each dose-escalation cohort in order to define the MTD. For this study, the DLT observation period is defined as the first and second treatment cycle (Cycle 1 and 2). Adverse events occurring after the DLT observation period will also be reviewed and may be taken into consideration for dose escalation decisions. The feasible dose selected by the design will guide the determination of the preliminary RP2D.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
9/12/2022
Actual
30/06/2023
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
32
Accrual to date
12
Final
Recruitment in Australia
Recruitment state(s)
ACT,NSW,NT,QLD,SA,TAS,WA,VIC
Recruitment hospital [1] 26838 0
The Royal Adelaide Hospital - Adelaide
Recruitment hospital [2] 26839 0
Royal Darwin Hospital - Tiwi
Recruitment hospital [3] 26840 0
Monash Medical Centre - Clayton campus - Clayton
Recruitment hospital [4] 26841 0
Calvary Mater Newcastle - Waratah
Recruitment postcode(s) [1] 42893 0
5000 - Adelaide
Recruitment postcode(s) [2] 42894 0
0810 - Tiwi
Recruitment postcode(s) [3] 42895 0
3168 - Clayton
Recruitment postcode(s) [4] 42896 0
2298 - Waratah
Recruitment outside Australia
Country [1] 24060 0
New Zealand
State/province [1] 24060 0

Funding & Sponsors
Funding source category [1] 309524 0
Other Collaborative groups
Name [1] 309524 0
Australasian Leukaemia and Lymphoma Group
Country [1] 309524 0
Australia
Primary sponsor type
Other Collaborative groups
Name
Australasian Leukaemia and Lymphoma Group
Address
35 Elizabeth Street,
Richmond
VIC 3121
Country
Australia
Secondary sponsor category [1] 310509 0
None
Name [1] 310509 0
none
Address [1] 310509 0
none
Country [1] 310509 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 309305 0
Bellberry Human Research Ethics Committee
Ethics committee address [1] 309305 0
123 Glen Osmond Road
Eastwood SA 5063
Ethics committee country [1] 309305 0
Australia
Date submitted for ethics approval [1] 309305 0
30/11/2022
Approval date [1] 309305 0
18/08/2023
Ethics approval number [1] 309305 0
2023/ETH00087
Ethics committee name [2] 315251 0
Central Adelaide Local Health Network
Ethics committee address [2] 315251 0
North Terrace
Adelaide, SA, 5000
Ethics committee country [2] 315251 0
Australia
Date submitted for ethics approval [2] 315251 0
25/03/2022
Approval date [2] 315251 0
18/08/2022
Ethics approval number [2] 315251 0
2022/HRE00054

Summary
Brief summary
High risk MDS is a challenging condition with limited treatment options. Patients often depend on blood transfusions and unfortunately chemotherapy is rarely successful as a treatment option. The main type of therapy used in MDS are hypomethylating agents (HMAs) such as Azacitidine (AZA) and Decitabine (DEC). Traditionally, combination therapy has not proven to be effective in MDS given the increased toxicity of drugs used in combination with AZA, even where the overall responses may have been promising. Therefore, this trial aims to test a relatively non-cytotoxic drug called ES-3000, in combination with a HMA named ASTX727.
Who is it for?
You may be eligible to join this study if you are aged 16 years or above, and have a diagnosis of MDS or acute myeloid leukaemia (AML) with <30% blasts.

Trial details:
All participants will receive treatment in 28-day cycles. At first, each participant will receive a single cycle of ES-3000 alone, in order to take blood samples at various timepoints throughout the day to establish how the drug is metabolised by the body. ES-3000 is an oral tablet administered three times per day on days 1-14 of the cycle. Each subsequent participant recruited to the trial will receive a higher dose of ES-3000, until the dose is no longer tolerated. From the second cycle onwards, participants will receive the same dose of ES-3000 in combination with a previously established safe dose of ASTX727 once per day on days 1-5 of each cycle. This will continue until the participant experiences either unacceptable toxicity, or disease progression. Participants will be monitored for adverse effects for the duration of treatment, as well as every 3 months for assessment of their response to treatment through blood samples and bone marrow biopsies, and assessment of quality of life through completion of a questionnaire.

It is hoped that this study may show that ES-3000 administered in combination with Inqovi is safe and effective for the treatment of MDS and AML. This study may help to inform the dosing of ES-3000 required for patients with these conditions in future.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 113702 0
A/Prof Anoop Enjeti
Address 113702 0
Calvary Mater Newcastle
Level 4, New Med Bldg, Edith Street
Waratah NSW 2298
Country 113702 0
Australia
Phone 113702 0
+61 0240143021
Fax 113702 0
Email 113702 0
[email protected]
Contact person for public queries
Name 113703 0
Delaine Smith
Address 113703 0
ALLG
35 Elizabeth Street,
Richmond
VIC 3121
Country 113703 0
Australia
Phone 113703 0
+61 03 8373 9701
Fax 113703 0
Email 113703 0
[email protected]
Contact person for scientific queries
Name 113704 0
Delaine Smith
Address 113704 0
ALLG
35 Elizabeth Street,
Richmond
VIC 3121
Country 113704 0
Australia
Phone 113704 0
+61 03 8373 9701
Fax 113704 0
Email 113704 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Individual patient data will not be shared publically. Aggregate patient data and final results will be presented in the final report.


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.