MDS05/D2 - Phase Ib/II study for treatment of Myelodysplasia (MDS) with SRA515 and ASTX727,
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).
Australasian Leukaemia and Lymphoma Group (ALLG)
86 participants
Mar 1, 2023
Interventional
Conditions
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.
Eligibility
Inclusion Criteria6
- Provision of written informed consent
- Provision of written informed consent to the Australasian Leukaemia and Lymphoma Group National Blood Cancer Registry (ALLG NBCR)
- Age 18 and above (Age 16-17 permitted if consent for minor PICF approved by the authorising HREC)
- A diagnosis of MDS or Acute Mueloid Leukaemia (AML) with less than 30% blasts
- Treatment naïve myelodysplasia patients with IPSS score equal to 1.5 and be eligible for standard HMA treatment in Australia.
- AML with blasts less than 30% will also be eligible for this domain of the study.
Exclusion Criteria20
- History of other malignancy requiring active systemic treatment, or which is likely to result in an expected survival time of less than 12 months.
- Viral infection with known HIV or viral hepatitis type B or C not adequately controlled by antiviral medication
- Prior allogeneic bone marrow, HSCT or solid organ transplantation
- Subjects with QTcF greater than 480msecs, confirmed by repeat ECG
- Left Ventricular Ejection Fraction (LVEF) of less than 50%
- Use of parenteral anticoagulants at therapeutic levels, warfarin or direct oral anticoagulants within 7 days prior to the first dose of SRA515
- 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)
- Subjects with active bleeding and/or clinically significant bleeding in the last 12 months.
- 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
- Subject has a known positive test for human immunodeficiency virus (HIV). Note: HIV testing is not required at Screening.
- Subject has chronic active hepatitis B (HBV) or hepatitis C (HCV) requiring treatment.
- 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.
- Subject has a malabsorption syndrome or other condition that precludes an enteral route of administration.
- 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.
- Subject is concurrently participating in another therapeutic clinical trial.
- Subject is pregnant or breastfeeding.
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Interventions
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.
Locations(1)
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ACTRN12622001302741