Combined Evaluation of Epigenetic and Sensitising Therapy in AML and MDS (CELESTIAL-MDS)

Inclusion Criteria: 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. Exclusion Criteria: Participants who meet any of the following criteria at the time of screening/enrolment (up to 28 days prior to Cycle 1 Day 1) will be ineligible for entry into the study: Acute myeloid leukemia (AML) with ≥ 30% blasts in bone marrow according to WHO classification. Prior allogeneic or autologous stem cell transplant. Prior receipt of >1 cycle of a hypomethylating agent. Clinical evidence of central nervous system (CNS) or pulmonary leukostasis, disseminated intravascular coagulation, or CNS leukemia. Use of any of the following within 28 days prior to cycle 1 day 1: thrombopoiesis-stimulating agents ([TSAs]; eg, Romiplostim, Eltrombopag, Interleukin-11) ESAs (Erythropoiesis stimulating agent) and other RBC (Red blood cell) hematopoietic growth factors (eg, interleukin-3) Any other investigational medicinal product from another clinical trial. Exposure to any medication, supplement, traditional/herbal medicine, or food with potential for drug-drug interactions with defactinib during the course of the study. This includes: strong CYP3A4 inhibitors or inducers strong CYP2C9 inhibitors or inducers P-glycoprotein (P-gp) inhibitors or inducers Treatment with warfarin. Patients on warfarin can be converted to low molecular-weight heparin or direct oral anticoagulants (DOACs). Participants unwilling or unable to convert to an alternative are not eligible. Use of hydrea for more than 7 days prior to cycle 1 day 1. Use within that time period is permissible. Concurrent use of corticosteroids unless the participant is on a dose of ≤10mg prednisolone or equivalent for medical conditions other than MDS. Active inflammatory bowel disease, or any other gastrointestinal disorder or defect that would interfere with the ingestion, absorption, distribution, metabolism or excretion of the investigational products and/or predispose the participant to an increased risk of gastrointestinal toxicity. Prior history of malignancies, other than MDS unless the participant has been free of the disease for ≥ 12 months. However, participants with the following history/concurrent conditions are allowed: Basal or squamous cell carcinoma of the skin Carcinoma in situ of the cervix Carcinoma in situ of the breast Incidental histologic finding of prostate cancer (T1a or T1b using the tumor, nodes, metastasis [TNM] clinical staging system) Significant active cardiac disease within the previous 6 months, including: New York Heart Association (NYHA) class III or IV congestive heart failure; Unstable angina or angina requiring surgical or medical intervention; and/or Myocardial infarction Baseline Qt interval greater than 440 milliseconds (males) or 450 milliseconds (females) Active systemic infection: Infection with ongoing signs/symptoms related to the infection without improvement despite appropriate anti- infectives Active Hepatitis B (HBV) infection (defined as HBsAg positive, or HBcAb positive and measurable HBV DNA; participants who are HBcAb positive must have HBV DNA assayed during screening) Participants with Human Immunodeficiency Virus (HIV) or Hepatitis C (HCV) infection will be considered individually by the coordinating principal investigator: Those with HIV will generally be eligible if receiving antiretroviral therapy, HIV viral load (VL) is suppressed <50 copies/mL , and CD4≥350 cells/mm3. Those with HCV will generally be eligible if there is no evidence of clinical hepatic dysfunction or other systemic manifestations of HCV disease and the hepatic parameters below are met. Consideration should be given to curative HCV therapy prior to enrollment in consultation with HCV clinician, if possible. Any of the following laboratory abnormalities: Serum AST/SGOT (Aspartate transaminase / Serum glutamic oxaloacetic transaminase) or ALT/SGPT (Alanine aminotransaminase / Serum glutamic pyruvate transaminase) > 2.5 x ULN (upper limit of normal) Serum total bilirubin > 1.5 x ULN. Patients with Gilbert syndrome may enroll if total bilirubin < 51 umol/L upon discussion with the coordinating investigator Evidence of autoimmune hemolytic anemia manifested as a corrected reticulocyte count of > 2% with either a positive direct anti-globulin test (DAT) or over 50% of indirect bilirubin Creatinine clearance <50 ml/minute as calculated by the CockcroftGault formula or serum creatinine of ≥ 1.5 x ULN. Absolute WBC (white blood cell count) ≥ 20 x 109/L f ) Participants with isolated individual lab abnormalities considered to be disease related will be considered individually in consultation with the Coordinating Principal Investigator. Known or suspected hypersensitivity to study drugs or their constituents. Pregnant or breast-feeding. Any condition not already outlined above which, in the opinion of the clinical investigator, would place the participant at risk if they participated or would jeopardise adherence or follow up or confound the ability to interpret study data.