Randomised Study of Oral Azacitidine vs Placebo Maintenance in AML or MDS Patients After Allo-SCT

Inclusion Criteria:

1. Age ≥ 16 at the time of signing the informed consent form

2. Patients with a diagnosis of any of the below:

• AML (CR1 or CR2) according to World Health Organization (WHO) classification;

• Secondary AML (defined as previous history of MDS, antecedent hematologicaldisease or chemotherapy exposure; CR1 or CR2); or

• Advanced or high risk MDS with an IPSS-R of ≥3.5 (intermediate 3.5 or higher)including intermediate or high risk chronic myelomonocytic leukaemia (CMML) (e.g. CPSS int-2 or high risk) (as per IPSS-R) undergoing allo-SCT using myeloablative conditioning (MAC) or reduced-intensityconditioning (RIC) preparative regimens, and with either peripheral blood or bonemarrow as the source of hematopoietic stem cells.

3. At the time of allo-SCT

• No prior allo-SCT; and

• No more than 1 antigen mismatch at HLA-A, -B, -C, -DRB1 or -DQB1 locus foreither related or unrelated donor; and

• No haplotype or cord blood donor; and

• Bone marrow blast <5% for AML and <10% for MDS patients

4. Able to commence therapy between 42 to 84 days following allo-SCT

5. Post-transplant bone marrow

6. AML patients - blast count ≤ 5% confirmed within 28 days prior to startingstudy therapy

7. MDS patients - confirmation of CR post-transplant with blast count ≤ 5% in bonemarrow

8. Adequate neutrophil and platelet engraftment within 14 days prior to starting studytherapy defined as:

• Absolute neutrophil count (ANC) ≥ 1.0 x 10^9/L on two consecutive testingwithout daily use of myeloid growth factor; and

• Platelet ≥ 50 x 10^9/L on two consecutive testing without platelet transfusionwithin 1 week

7. Adequate organ function:

• Serum aspartate aminotransferase (AST) and alanine transaminase (ALT) < 4 xupper limit of normal (ULN)

• Serum bilirubin < 2 x ULN. Higher levels are acceptable if these can beattributed to active red blood cell (RBC) precursor destruction within the bonemarrow (i.e., ineffective erythropoiesis) or Gilbert's syndrome

• Serum creatinine < 2 x ULN

8. Adequate coagulation (Prothrombin time (PT) ≤ 15 seconds and partial thromboplastintime (PTT) ≤ 40 seconds)

9. Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2

10. Patients with adequately controlled GVHD (defined as GVHD grade <II with concurrentuse of corticosteroids equivalent of prednisone at a dose ≤ 0.5 mg/kg) can beincluded

11. Females of childbearing potential (FCBP) may participate, providing they meet thefollowing conditions:

12. Agree to use at least two effective contraceptive methods (oral, injectable, orimplantable hormonal contraceptive; tubal ligation; intra-uterine device;barrier contraceptive with spermicide; or vasectomised partner) or practicetrue abstinence throughout the study, and for 6 months following the last doseof study therapy and

13. Have a negative serum pregnancy test (sensitivity of at least 25 mIU/mL) atscreening; and

14. Have a negative serum or urine (investigator's discretion) pregnancy test (sensitivity of at least 25 mIU/mL) within 72 hours prior to starting studytherapy. This applies even if the subject practices complete abstinence fromheterosexual contact.

15. Male patients with a female partner of childbearing potential must agree to the useof at least two physician-approved contraceptive methods throughout the course ofthe study and should avoid fathering a child during the course of the study and for 3 months following the last dose study therapy

16. Understand and voluntarily sign an informed consent from prior to any study relatedassessments or procedures being conducted

17. Able to adhere to the study visit schedule (i.e., clinic visits at the study sitesare mandatory, unless noted otherwise for study visits) and other protocolrequirements

Exclusion Criteria:

1. Use of any of the following after transplantation and prior to starting studytherapy:

• Any chemotherapy used for adjuvant therapy

• Unlicensed investigational agents/therapies used within 28 days prior tostarting study therapy

• Azacitidine, decitabine or other hypomethylating agent (HMA)

• Lenalidomide, thalidomide and pomalidomide used within 28 days prior tostarting study therapy

2. Subjects who have undergone a haploidentical or cord blood transplant

3. Active GVHD grade II or higher (acute GVHD Clinical Staging and Grading)

4. Concurrent use of corticosteroids equivalent of prednisone at a dose > 0.5 mg/kg

5. Known active viral infection with Human Immunodeficiency Virus (HIV), Hepatitis BVirus (HBV) or Hepatitis C Virus (HCV)

6. Active uncontrolled systemic fungal, bacterial, or viral infection (defined asongoing signs/symptoms related to the infection without improvement despiteappropriate antibiotics, antiviral therapy, and/or other treatment)

7. History of inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis),celiac disease (i.e., sprue), prior gastrectomy or upper bowel removal, or any otherGI disorder or defect that may interfere with the absorption, distribution,metabolism or excretion of the investigational medicinal products (IMPs) and/orpredispose the subject to an increased risk of gastrointestinal toxicity prior toallo-SCT

8. Idiopathic thrombocytopenic purpura (ITP), disseminated intravascular coagulation,haemolytic uremic syndrome, thrombotic thrombocytopenic purpura (TTP)

9. History of prior malignancies, except: lobular breast carcinoma in situ, fullyresected basal cell or squamous cell carcinoma of skin or treated cervical carcinomain situ, Incidental histologic finding of prostate cancer (T1a or T1b using thetumor, node, metastasis (TNM) clinical staging system), previous MDS, CMML,myeloproliferative neoplasms (MPN) resulting in secondary AML. Cancer treated withcurative intent ≥ 5 years previously will be allowed. Cancer treated with curativeintent < 5 years previously will not be allowed.

10. 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

11. Known or suspected hypersensitivity to azacitidine or mannitol

12. Pregnant or lactating females

13. Any significant medical condition, laboratory abnormality, or psychiatric illnessthat would prevent the patient from participating in the study.

14. Any condition including the presence of laboratory abnormalities, which places thepatient at unacceptable risk if he/she were to participate in the study

15. Any condition that confounds the ability to interpret data from the study