Combined Evaluation of Epigenetic and Sensitising Therapy in AML and MDS

Inclusion Criteria:

Participants must meet all of the following criteria at the time of screening:

1. Age ≥ 18 years

2. Documented diagnosis of:

3. Myelodysplastic syndrome (MDS) classified as intermediate-2 or high riskaccording to the International Prognostic Scoring System (IPSS), or

4. Acute Myeloid Leukaemia (AML) with 20-30% marrow blasts and multilineagedysplasia, according to WHO classification, or

5. Chronic myelomonocytic leukemia (CMML) with 10-29% marrow blasts withoutmyeloproliferative 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 6weeks before cycle 1 day 1.

6. Performance status by Eastern Cooperative Oncology Group (ECOG) Criteria of 0 or 1

7. Unsuitable for allogeneic stem cell transplantation

8. For participants who were born female who are of childbearing potential (FCBP) thefollowing criteria apply:

9. Agreement to use at least two highly effective (per Clinical Trial FacilitationGroup) contraceptive methods throughout the study, and for 6 months followingthe last dose of study drug:

• Oral/intravaginal/transdermal combined (estrogen and progestogencontaining) hormonal contraception associated with inhibition of ovulation
• Oral/injectable/implantable progestogen-only hormonal contraceptionassociated with inhibition of ovulation
• Intrauterine device (IUD)
• Intrauterine hormone-releasing system (IUS)
• Bilateral tubal occlusion
• Vasectomised partner
• Sexual abstinence and

2. Confirmation of a negative serum pregnancy test at screening.

3. Male participants with a partner who was born female and is of childbearingpotential must agree to use at least two highly effective (per Clinical TrialFacilitation Group) contraceptive methods throughout the course of the study and for 6 months following the last dose of study drug, and refrain from donating spermduring the same period

4. Provision of signed written informed consent document prior to any study relatedassessments 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:

1. Acute myeloid leukemia (AML) with ≥ 30% blasts in bone marrow according to WHOclassification.

2. Prior allogeneic or autologous stem cell transplant.

3. Prior receipt of >1 cycle of a hypomethylating agent.

4. Clinical evidence of central nervous system (CNS) or pulmonary leukostasis,disseminated intravascular coagulation, or CNS leukemia.

5. Use of any of the following within 28 days prior to cycle 1 day 1:

6. thrombopoiesis-stimulating agents ([TSAs]; eg, Romiplostim, Eltrombopag,Interleukin-11)

7. ESAs (Erythropoiesis stimulating agent) and other RBC (Red blood cell)hematopoietic growth factors (eg, interleukin-3)

8. Any other investigational medicinal product from another clinical trial.

9. Exposure to any medication, supplement, traditional/herbal medicine, or food withpotential for drug-drug interactions with defactinib during the course of the study.This includes:

10. strong CYP3A4 inhibitors or inducers

11. strong CYP2C9 inhibitors or inducers

12. P-glycoprotein (P-gp) inhibitors or inducers

13. Treatment with warfarin. Patients on warfarin can be converted to lowmolecular-weight heparin or direct oral anticoagulants (DOACs). Participantsunwilling or unable to convert to an alternative are not eligible.

14. Use of hydrea for more than 7 days prior to cycle 1 day 1. Use within that timeperiod is permissible.

15. Concurrent use of corticosteroids unless the participant is on a dose of ≤10mgprednisolone or equivalent for medical conditions other than MDS.

16. Active inflammatory bowel disease, or any other gastrointestinal disorder or defectthat would interfere with the ingestion, absorption, distribution, metabolism orexcretion of the investigational products and/or predispose the participant to anincreased risk of gastrointestinal toxicity.

17. Prior history of malignancies, other than MDS unless the participant has been freeof the disease for ≥ 12 months. However, participants with the followinghistory/concurrent conditions are allowed:

18. Basal or squamous cell carcinoma of the skin

19. Carcinoma in situ of the cervix

20. Carcinoma in situ of the breast

21. Incidental histologic finding of prostate cancer (T1a or T1b using the tumor,nodes, metastasis [TNM] clinical staging system)

22. Significant active cardiac disease within the previous 6 months, including:

23. New York Heart Association (NYHA) class III or IV congestive heart failure;

24. Unstable angina or angina requiring surgical or medical intervention; and/or

25. Myocardial infarction

26. Baseline Qt interval greater than 440 milliseconds (males) or 450 milliseconds (females)

27. Active systemic infection:

28. Infection with ongoing signs/symptoms related to the infection withoutimprovement despite appropriate anti- infectives

29. Active Hepatitis B (HBV) infection (defined as HBsAg positive, or HBcAbpositive and measurable HBV DNA; participants who are HBcAb positive must haveHBV DNA assayed during screening)

30. Participants with Human Immunodeficiency Virus (HIV) or Hepatitis C (HCV)infection will be considered individually by the coordinating principalinvestigator:

• Those with HIV will generally be eligible if receiving antiretroviraltherapy, HIV viral load (VL) is suppressed <50 copies/mL , and CD4≥350cells/mm3.
• Those with HCV will generally be eligible if there is no evidence ofclinical hepatic dysfunction or other systemic manifestations of HCVdisease and the hepatic parameters below are met. Consideration should begiven to curative HCV therapy prior to enrollment in consultation with HCVclinician, if possible.

15. Any of the following laboratory abnormalities:

16. Serum AST/SGOT (Aspartate transaminase / Serum glutamic oxaloacetictransaminase) or ALT/SGPT (Alanine aminotransaminase / Serum glutamic pyruvatetransaminase) > 2.5 x ULN (upper limit of normal)

17. Serum total bilirubin > 1.5 x ULN. Patients with Gilbert syndrome may enroll iftotal bilirubin < 51 umol/L upon discussion with the coordinating investigator

18. Evidence of autoimmune hemolytic anemia manifested as a corrected reticulocytecount of > 2% with either a positive direct anti-globulin test (DAT) or over 50% of indirect bilirubin

19. Creatinine clearance <50 ml/minute as calculated by the CockcroftGault formulaor serum creatinine of ≥ 1.5 x ULN.

20. Absolute WBC (white blood cell count) ≥ 20 x 109/L f ) Participants withisolated individual lab abnormalities considered to be disease related will beconsidered individually in consultation with the Coordinating PrincipalInvestigator.

21. Known or suspected hypersensitivity to study drugs or their constituents.

22. Pregnant or breast-feeding.

23. Any condition not already outlined above which, in the opinion of the clinicalinvestigator, would place the participant at risk if they participated or wouldjeopardise adherence or follow up or confound the ability to interpret study data.