Acute myeloid leukaemia, myelodysplastic syndromes Cancer
Conditions
Interventions
Patients will be randomised 1:1 to either treatment with oral azacitidine (CC-486) or matching placebo. Patients will take a dose of 200 mg once daily from days 1 – 14 of a 28-day cycle. Patients will
Sponsors
University of Birmingham
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: Current participant inclusion criteria as of 24/02/2021: 1. Age = 16 years at the time of signing the informed consent form 2. Patients with a diagnosis of any of the below and undergoing allo-SCT using MAC or RIC preparative regimens, and with either peripheral blood or bone marrow as the source of hematopoietic stem cells: 2.1. AML (CR1 or CR2) according to WHO classification 2.2. Secondary AML (defined as a previous history of MDS, antecedent hematological disease, or chemotherapy exposure; CR1 or CR2) 2.3. Advanced or high-risk MDS with an IPSS-R of =3.5 (intermediate 3.5 or higher) including intermediate or high-risk CMML (e.g. CPSS int-2 or high risk) 3. At the time of allo-SCT 3.1. No prior allo-SCT 3.2. No more than 1 antigen mismatch at HLA-A, -B, -C, -DRB1 or -DQB1 locus for either related or unrelated donor 3.3. No haplotype or cord blood donor 3.4. Bone marrow blast <5% for AML and <10% for MDS patients 4. Able to commence study therapy between 42 to 84 days following allo-SCT 5. Post-transplant bone marrow: 5.1. AML patients – blast count =5% confirmed within 28 days prior to starting study therapy 5.2. MDS patients – confirmation of CR post-transplant with blast count =5% in bone marrow 6. Adequate neutrophil and platelet engraftment within 14 days prior to starting study therapy defined as: 6.1. ANC =1.0 x 109/l on two consecutive testing without daily use of myeloid growth factor 6.2. Platelet = 50 x 109/l on two consecutive testing without platelet transfusion within 1 week 7. Adequate organ function: 7.1. Serum AST or ALT <3 x upper limit of normal (ULN) 7.2. Serum bilirubin <2 x ULN. Higher levels are acceptable if these can be attributed to active red blood cell (RBC) precursor destruction within the bone marrow (i.e., ineffective erythropoiesis) or Gilbert’s syndrome. 7.3. Serum creatinine <2 x ULN 8. Adequate coagulation (PT =15 s and PTT =40 s) 9. Eastern Cooperative Oncology Group (ECOG) performance status of =2 10. Patients with adequately controlled GVHD (defined as GVHD grade <II with concurrent use of corticosteroids equivalent of prednisone at a dose =0.5 mg/kg) can be included 11. Females of childbearing potential may participate, providing they meet the following conditions: 11.1. Agree to use at least two effective contraceptive methods (oral, injectable, or implantable hormonal contraceptive; tubal ligation; intra-uterine device; barrier contraceptive with spermicide; or vasectomised partner) or practice true abstinence throughout the study, and for 3 months following the last dose of study therapy 11.2. Have a negative serum or urine pregnancy test (sensitivity of at least 25 mIU/mL) at screening 11.3. Have a negative serum or urine (investigator’s discretion) pregnancy test (sensitivity of at least 25 mIU/ml) within 72 h prior to starting study therapy. This applies even if the subject practices complete abstinence from heterosexual contact. 12. Male patients with a female partner of childbearing potential must agree to the use of at least two physician-approved contraceptive methods throughout the course of the study and should avoid fathering a child during the course of the study and for 3 months following the last dose study therapy 13. Understand and voluntarily sign an informed consent form (ICF) prior to any study-related assessments or procedures being conducted 14. Able to adhere to the study visit schedule (i.e., clinic visits at the study sites are mandatory unless noted otherwise fo
Exclusion criteria
Exclusion criteria: Current participant exclusion criteria as of 24/02/2021: 1. Use of any of the following after transplantation and prior to starting study therapy: 1.1. Any agents (chemotherapy or targeted agents) used for adjuvant therapy (note that prophylactic use of these agents is allowed in this study, e.g., methotrexate for GVHD or rituximab for EBV reactivation) 1.2. Unlicensed investigational agents/therapies used within 28 days prior to starting study therapy 1.3. Azacitidine, decitabine or other hypomethylating agent (HMA) 1.4. Lenalidomide, thalidomide and pomalidomide used within 28 days prior to starting study therapy 1.5. Any chemotherapy used for adjuvant 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 B Virus (HBV) or Hepatitis C Virus (HCV) 6. Active uncontrolled systemic fungal, bacterial, or viral infection (defined as ongoing signs/symptoms related to the infection without improvement despite appropriate 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 other GI disorder or defect that may interfere with the absorption, distribution, metabolism or excretion of the investigational medicinal products (IMPs) and/or predispose the subject to an increased risk of gastrointestinal toxicity prior to allo-SCT 8. Idiopathic thrombocytopenic purpura (ITP), disseminated intravascular coagulation, haemolytic uremic syndrome, thrombotic thrombocytopenic purpura (TTP) 9. History of prior malignancies. However, the following will be exceptions: 9.1. Fully resected basal cell or squamous cell carcinoma of skin 9.2. Treated cervical carcinoma in situ 9.3. Lobular breast carcinoma in situ, 9.4. Incidental histologic finding of prostate cancer (T1a or T1b using the tumor, node, metastasis clinical staging system) 9.5. Previous Myelodysplastic Syndrome (MDS), Chronic Myelomonocytic Leukemia (CMML), Myeloproliferative Neoplasm (MPN) resulting in secondary acute myeloid leukaemia (AML) 9.6. Cancer treated with curative intent =5 years previously 10. Significant active cardiac disease within the previous 6 months, including: 10.1. New York Heart Association (NYHA) class III or IV congestive heart failure 10.2. Unstable angina or angina requiring surgical or medical intervention; and/or 10.3. 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 illness that would prevent the patient from participating in the study. 14. Any condition including the presence of laboratory abnormalities, which places the patient 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 Previous participant exclusion criteria: 1. Use of any of the following after transplantation and prior to starting study therapy: 1.1. Any agents (chemotherapy or targeted agents) used for adjuvant therapy (note that prophylactic use of these agents is allowed in this study, e.g., methotrexate for GVHD or rituximab for EBV r
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Relapse free survival; Timepoint(s): Date of first relapse (including morphological, cytogenetic or molecular relapse) or death from any cause. Patients who are progression free and still alive at the end of the trial will be censored at their date of last follow-up | — |
Secondary
| Measure | Time frame |
|---|---|
| 1. Overall survival is defined as the time from date of randomisation to date of death, from any cause. Patients who are alive at the end of the trial will be censored at their date last seen. 2. Cumulative incidence of relapse is defined as the time from date of randomisation to date of relapse. Patients who die without relapse will be considered a competing risk, at their date of death. Patients who are alive and relapse free at the end of the trial will be censored at their date last seen. 3. Non-relapse mortality is defined as the time from date of randomisation to date of any death not following relapse. Patients who die post relapse will be considered a competing event at their date of death and patients who are alive at the end of the trial will be censored at their date last seen. 4. Incidence of acute and chronic GVHD of any grade reported throughout the trial. 5. Time to early treatment discontinuation is defined as the time from date of randomisation to date of treatment discontinuation, for any reason. Patients who take the full year of treatment will be censored at 12 months. 6. Safety will be collected in accordance with CTCAE criteria version 4.0 and defined as the number of patients who experience one or more adverse event. 7. Quality of life measured using the EORTC-QLQ-C30 and EQ-5D questionnaires at randomisation i.e. baseline and at 3, 6, 12 (end of treatment) and 24 months post randomisation 8. GVHD-free and relapse-free survival defined as time from date of randomisation to date of first event or death. An event is defined as GVHD or relapse (including molecular relapse and progression). Patients who are alive and event free at the end of the trials will be censored at their date last seen | — |
Countries
England, Scotland, United Kingdom, Wales
Outcome results
None listed