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Trial registered on ANZCTR


Registration number
ACTRN12622001302741p
Ethics application status
Not yet submitted
Date submitted
31/08/2022
Date registered
7/10/2022
Date last updated
7/10/2022
Date data sharing statement initially provided
7/10/2022
Type of registration
Prospectively registered

Titles & IDs
Public title
MDS05/D2 - Phase Ib/II study for treatment of Myelodysplasia (MDS) with SRA515 and ASTX727,
Scientific title
MDS05/D2 - A multicentre phase Ib/II open label randomized platform design study to determine the safety and efficacy of SRA515 and ASTX727 for treatment of intermediate and high risk Myelodysplastic Syndrome (MDS).
Secondary ID [1] 307861 0
ALLG: MDS05/D2
Universal Trial Number (UTN)
Trial acronym
Linked study record
This study is the second domain of the MYDAS-T MDS05 platform trial (Master Protocol registered under ACTRN12622000410752).

Health condition
Health condition(s) or problem(s) studied:
Myelodysplastic Syndrome (MDS) 327479 0
Acute Myeloid Leukaemia (AML) 327480 0
Condition category
Condition code
Cancer 324604 324604 0 0
Leukaemia - Acute leukaemia

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The MYDAS-T study is a multi-domain platform trial. Domain 2 is a Phase I/IIa, open-label, dose determination, dose-confirmation, safety and efficacy study of SRA515 and ASTX727 in subjects with intermediate and high risk MDS to be conducted in 2 parts:

Part 1: Phase Ib Safety and Dose-Determination (1 cycle)
This phase involves recruiting cohorts of 3 patients. All newly-recruited subjects will receive a fixed standard dose of ASTX727 via oral capsules (consisting of 35mg Decitabine and 100mg Ceduzuridine) on Days 1-5, to be administered once daily under 2 hr pre and 2 hr post dose fasting window. This is followed by a starting daily dose of 10 mg of SRA515 via oral capsules on days 6-15. Dose limiting toxicities (DLTs) will be monitored during this time. Based on the DLT's observed after one cycle of treatment, patients will move on to Part 2 with their dose of SRA515 increased, decreased or remaining the same. If there are no DLTs observed the dose will increase by 5mg. If there are DLTs observed, the dose will be decreased by 5mg.
Patients who do not experience a DLT will be evaluable if they receive at least 75% of the dose in each of cycles 1 (i.e. at least 4 days of the full daily dose for ASTX and 8 days of the full daily dose for SRA515).

Part 2: Phase II Dose-Expansion
Once all subjects complete Part 1, the recommended phase 2 dose (RP2D) can be determined and an additional 60 MDS subjects (depending on the number recruited in the dose finding phase) will be enrolled in Part II (Phase II) of the study for a minimum of 6 cycles. Recruitment will commence to part 2 approximately 4 weeks once recruitment closes on part 1. In Part 2, patients will continue receiving the fixed dose of ASTX727 (consisting of 35mg Decitabine and 100mg Ceduzuridine) on days 1-5 and the RP2D of SRA515 (as determined in part 1) on days 6-15 of each 28-day cycle until experiencing an event such as MDS progression/relapse, progression to Acute Myeloid Leukaemia (AML), withdrawal of consent or unaccepted toxicity.

Patients will be monitored at their standard of care clinic visits and associated tests eg bone marrow aspiration, blood tests, physical examinations. Patients will only move on to the next consecutive phase once the previous phase is completed. All treatment will be administered by the study team. Drug accountability will be performed by the administering institutions to assess compliance.
Intervention code [1] 324329 0
Treatment: Drugs
Comparator / control treatment
There is no comparator arm
Control group
Uncontrolled

Outcomes
Primary outcome [1] 332421 0
To determine the safety and tolerability of SRA515 in combination with ASTX727. This will be completed by reviewing the patients blood biochemistry markers, peripheral blood counts for adverse events.
Timepoint [1] 332421 0
After all patients have completed day 28 cycle 2 post-intervention commencement
Primary outcome [2] 332424 0
To determine the Recommended Phase 2 Dose (RP2D) for the expansion phase of the trial. This will be completed by reviewing the patients blood biochemistry markers, peripheral blood counts for adverse events.
Timepoint [2] 332424 0
After an occurrence of a Dose-Limiting Toxicity (DLT) event related to any one of the treatments i.e. SRA515 and ASTX727. Examples if such DLTs include low platelet count, low neutrophil count or hypo-cellular bone marrow.
Primary outcome [3] 332425 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] 332425 0
At 3 and 6 months after treatment commencement
Secondary outcome [1] 413446 0
To assess event free survival (EFS) calculated using blood and bone markers indicating response.
Timepoint [1] 413446 0
After 6months of treatment, at the end of treatment, and when all patients have completed 5 years of follow up from end of treatment. Participants reach "End of treatment" after completing 6 cycles of Part 2 or when they experience disease progression or unacceptable toxicity.
Secondary outcome [2] 413447 0
To assess Overall Survival (OS) calculated for all patients utilizing the date the patient passed away. This will be sourced from medical records.
Timepoint [2] 413447 0
Rates will be assessed after 6 months of treatment, at the end of treatment and after 5 years of follow up from end of treatment . Participants reach "End of treatment" after completing 6 cycles of Part 2 or when they experience disease progression or unacceptable toxicity.
Secondary outcome [3] 413448 0
To assess Time to response (TTR) determined by blood and bone markers.
Timepoint [3] 413448 0
This will be calculated after 6months of treatment, at the end of all treatment and after 5 yrs of follow up from end of treatment . Participants reach "End of treatment" after completing 6 cycles of Part 2 or when they experience disease progression or unacceptable toxicity.
Secondary outcome [4] 413449 0
To assess Time to Transfusion Independence (T2TI) sourced by the number of transfusions given to the patient. This data will be obtained from review of medical records.
Timepoint [4] 413449 0
This will be assessed after 6months of treatment and at the end of treatment. Participants reach "End of treatment" after completing 6 cycles of Part 2 or when they experience disease progression or unacceptable toxicity.
Secondary outcome [5] 413450 0
To assess Quality of Life by having patients complete questionnaire EuroQOL EQ-5D
Timepoint [5] 413450 0
This will be analysed at the end of treatment and after 5 years of follow up from end of treatment . Participants reach "End of treatment" after completing 6 cycles of Part 2 or when they experience disease progression or unacceptable toxicity.
Secondary outcome [6] 413451 0
To conduct Frailty Assessments using the Instrumental "Activities of Daily Living Scale" Examination.
Timepoint [6] 413451 0
These will be analyzed at the end of treatment and after 5 years of follow up from end of treatment . Participants reach "End of treatment" after completing 6 cycles of Part 2 or when they experience disease progression or unacceptable toxicity. .
Secondary outcome [7] 413991 0
To conduct Frailty Assessments using the "Timed up and Go" Examination.
Timepoint [7] 413991 0
These will be analyzed at the end of treatment and after 5 years of follow up from end of treatment . Participants reach "End of treatment" after completing 6 cycles of Part 2 or when they experience disease progression or unacceptable toxicity.
Secondary outcome [8] 413992 0
To conduct Frailty Assessments using the Standardised Mini-Mental State Examination.
Timepoint [8] 413992 0
These will be analyzed at the end of treatment and after 5 years of follow up from end of treatment . Participants reach "End of treatment" after completing 6 cycles of Part 2 or when they experience disease progression or unacceptable toxicity.
Secondary outcome [9] 413993 0
To assess Quality of Life by having patients complete questionnaire EORTC QLQ-C30
Timepoint [9] 413993 0
This will be analysed at the end of treatment and after 5 years of follow up from end of treatment . Participants reach "End of treatment" after completing 6 cycles of Part 2 or when they experience disease progression or unacceptable toxicity.

Eligibility
Key inclusion criteria
1. Provision of written informed consent
2. Provision of written informed consent to the Australasian Leukaemia and Lymphoma Group National Blood Cancer Registry (ALLG NBCR)
3. Age 18 and above (Age 16-17 permitted if consent for minor PICF approved by the authorising HREC)
4. A diagnosis of MDS or Acute Mueloid Leukaemia (AML) with less than 30% blasts
5. Treatment naïve myelodysplasia patients with IPSS score equal to 1.5 and be eligible for standard HMA treatment in Australia.
6. AML with blasts less than 30% will also be eligible for this domain of the study.
Minimum age
16 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. History of other malignancy requiring active systemic treatment, or which is likely to result in an expected survival time of less than 12 months.
2. Viral infection with known HIV or viral hepatitis type B or C not adequately controlled by antiviral medication
3. Prior allogeneic bone marrow, HSCT or solid organ transplantation
4. Subjects with QTcF greater than 480msecs, confirmed by repeat ECG
5. Left Ventricular Ejection Fraction (LVEF) of less than 50%
6. Use of parenteral anticoagulants at therapeutic levels, warfarin or direct oral anticoagulants within 7 days prior to the first dose of SRA515
7. Coagulation parameters (prothrombin time/international normalised ratio [PT/INR] and activated partial thromboplastin time [APTT] of greater than or equal to 1.5 x the upper limit of normal (ULN)
8. Subjects with active bleeding and/or clinically significant bleeding in the last 12 months.
9. 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
10. Subject has a known positive test for human immunodeficiency virus (HIV). Note: HIV testing is not required at Screening.
11. Subject has chronic active hepatitis B (HBV) or hepatitis C (HCV) requiring treatment.
12. Subject exhibits evidence of other clinically significant uncontrolled condition(s) including, but not limited to ongoing systemic infection (viral, bacterial, or fungal). Note: Does not apply to Cohort 1 or Safety Expansion Cohort.
13. Subject has a malabsorption syndrome or other condition that precludes an enteral route of administration.
14. Subject has history of a significant cardiovascular (e.g. LVEF less than 50%), 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 needs a discussion between the investigator and study team.
15. Subject is concurrently participating in another therapeutic clinical trial.
16. 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 is an open label, Phase Ib/II trial with a randomized platform design study to determine the safety and efficacy of adding SRA515 to ASTX727 in subjects with intermediate and high risk MDS. The initial dose determining part of the trial will be followed by an expansion safety cohort. Up to 26 subjects will be recruited for the dose-determining phase (Phase Ib) and at least a further 60 patients in the dose expansion phase.
Dose Limiting Toxicities (DLTs) will be assessed during each dose-escalation cohort in order to define the Maximum Tolerated Dose (MTD). For this study, the DLT observation period is defined as the first treatment cycle (Cycle 1). Adverse events occurring after the DLT observation period will also be reviewed and may be taken into consideration for dose escalation decisions. Pharmacokinetic data will be collected during the DLT observation period of the dose escalation portion. The feasible dose selected by the Bayesian optimal interval (BOIN) design will guide the determination of the preliminary RP2D and phase II.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
1/03/2023
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
86
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
ACT,NSW,NT,QLD,SA,TAS,WA,VIC
Recruitment outside Australia
Country [1] 24987 0
New Zealand
State/province [1] 24987 0

Funding & Sponsors
Funding source category [1] 312138 0
Other Collaborative groups
Name [1] 312138 0
Australasian Leukaemia and Lymphoma Group (ALLG)
Country [1] 312138 0
Australia
Primary sponsor type
Other Collaborative groups
Name
Australasian Leukaemia and Lymphoma Group (ALLG)
Address
Ground Floor, 35 Elizabeth Street, Richmond VIC 3121
Country
Australia
Secondary sponsor category [1] 313658 0
None
Name [1] 313658 0
None
Address [1] 313658 0
None
Country [1] 313658 0

Ethics approval
Ethics application status
Not yet submitted
Ethics committee name [1] 311532 0
Central Adelaide Local Health Network Human Research Ethics Committee
Ethics committee address [1] 311532 0
Central Adelaide Local Health Network Human Research
Ethics Committee
Level 3, Roma Mitchell House
136 North Terrace
Adelaide, South Australia, 5000
Ethics committee country [1] 311532 0
Australia
Date submitted for ethics approval [1] 311532 0
24/12/2022
Approval date [1] 311532 0
Ethics approval number [1] 311532 0

Summary
Brief summary
This is an open label, Phase Ib/II trial with a randomized platform design study for treatment of myelodysplasia. The purpose of this trial is to determine the safety and efficacy of treatment by adding SRA515 to ASTX727 in intermediate and high risk MDS.
This multi-centre trial will recruit participants across Australia and New Zealand. Up to 26 subjects will be recruited for the dose-determining phase (Phase Ib) and at least a further 60 patients in the dose expansion phase.

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.

Study Details
This study will be conducted in two phases with cycles of 28 days. Phase Ib (Safety and Dose-Determination) will determine safety, tolerability and Recommended Phase II Dose (RP2D). Subjects will receive 35mg of ASTX727 by oral capsule on Days 1-5 of each cycle followed by a starting dose of 10mg of SRA515 by oral capsule on days 6-15.
Phase II (Dose-Expansion) will assess preliminary signs of efficacy by monitoring overall response rates in participants for a minimum of 6 cycles. Patients will continue receiving therapy until experiencing an event as detailed in the MDS05 Master Protocol.
During treatment participants will be assessed routinely for treatment-related toxicity events and investigators will modify treatment dosage or, if necessary, discontinue treatment. After treatment, disease will continue to be monitored and if participants have MDS progression or morphological relapse they will be assessed for the next best treatment option. It is hoped that the results of this trial will help determine if, and what dosage of, SRA515 in combination with ASTX727 is a safe and effective treatment option for patients with MDS or AML.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 121434 0
A/Prof Anoop Enjeti
Address 121434 0
Calvary Mater Newcastle Level 4, New Med Bldg, Edith Street Waratah NSW 2298
Country 121434 0
Australia
Phone 121434 0
+61 0240143021
Fax 121434 0
Email 121434 0
[email protected]
Contact person for public queries
Name 121435 0
Delaine Smith
Address 121435 0
ALLG 35 Elizabeth Street, Richmond VIC 3121
Country 121435 0
Australia
Phone 121435 0
+61 03 8373 9701
Fax 121435 0
Email 121435 0
[email protected]
Contact person for scientific queries
Name 121436 0
Delaine Smith
Address 121436 0
ALLG 35 Elizabeth Street, Richmond VIC 3121
Country 121436 0
Australia
Phone 121436 0
+61 03 8373 9701
Fax 121436 0
Email 121436 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.