A Phase I Study of Oral Decitabine and Cedazuridine (ASTX727) In Combination With Defactinib (VS-6063) as Therapy of Myelodysplastic Syndromes and Low-blast Acute Myeloid Leukaemia
The goal of this project is to see if two new potential treatments (defactinib and the combination tablet of decitabine/cedazuridine) can safely be combined to improve outcomes in people with high-risk myelodysplastic syndrome (MDS), certain forms of Acute Myeloid Leukaemia (AML), and Chronic Myelomonocytic Leukaemia (CMML). Decitabine/cedazuridine is approved for use by the Australian Therapeutics Goods Administration (TGA) as treatment for MDS. Defactinib is an experimental treatment. This means it is not an approved treatment for MDS in Australia. So far it has been given to over 625 patients in studies across the world. All study participants will receive active treatment, there is no placebo. Participants will take the decitabine/cedazuridine treatment once a day for 5 days in a row (day 1 to day 5) on its own for the first month (cycle). From month 2 participants will take the decitabine/cedazuridine treatment and will also take the defactinib treatment, both for 5 days in a row on days 1 to day 5 each month (cycle). Defactinib is taken twice a day.
⁃ Participants must meet all of the following criteria at the time of screening:
• Age ≥ 18 years
• Documented diagnosis of:
‣ Myelodysplastic syndrome (MDS) classified as intermediate-2 or high risk according to the International Prognostic Scoring System (IPSS), or
⁃ Acute Myeloid Leukaemia (AML) with 20-30% marrow blasts and multilineage dysplasia, according to WHO classification, or
⁃ Chronic myelomonocytic leukemia (CMML) with 10-29% marrow blasts without myeloproliferative disorder according to World Health Organisation (WHO) classification. This confirmation will be from either the Bone marrow aspirate (BMA) performed at screening or a standard of care BMA if performed up to 6 weeks before cycle 1 day 1.
• Performance status by Eastern Cooperative Oncology Group (ECOG) Criteria of 0 or 1
• Unsuitable for allogeneic stem cell transplantation
• For participants who were born female who are of childbearing potential (FCBP) the following criteria apply:
‣ Agreement to use at least two highly effective (per Clinical Trial Facilitation Group) contraceptive methods throughout the study, and for 6 months following the last dose of study drug:
• Oral/intravaginal/transdermal combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation
∙ Oral/injectable/implantable progestogen-only hormonal contraception associated with inhibition of ovulation
∙ Intrauterine device (IUD)
∙ Intrauterine hormone-releasing system (IUS)
∙ Bilateral tubal occlusion
∙ Vasectomised partner
∙ Sexual abstinence and
⁃ Confirmation of a negative serum pregnancy test at screening.
• Male participants with a partner who was born female and is of childbearing potential must agree to use at least two highly effective (per Clinical Trial Facilitation Group) contraceptive methods throughout the course of the study and for 6 months following the last dose of study drug, and refrain from donating sperm during the same period
• Provision of signed written informed consent document prior to any study related assessments or procedures being carried out.