Condition category
Cancer
Date applied
25/02/2019
Date assigned
25/02/2019
Last edited
04/06/2020
Prospective/Retrospective
Prospectively registered
Overall trial status
Ongoing
Recruitment status
Recruiting

Contact information

Type

Scientific

Primary contact

Dr Eszter Nagy

ORCID ID

Contact details

Haematology Team – IMPACT
Room 15
Centre for Clinical Haematology
Queen Elizabeth Hospital
Edgbaston
Birmingham
B15 2TH
United Kingdom
+44 (0)121 371 7858
e.nagy@bham.ac.uk

Additional identifiers

EudraCT number

2018-001012-30

ClinicalTrials.gov number

Protocol/serial number

41275

Study information

Scientific title

A double-blind, phase III, randomised study to compare the efficacy and safety of oral azacitidine (CC-486) versus placebo in subjects with acute myeloid leukaemia or myelodysplastic syndromes as maintenance after allogeneic haematopoietic stem cell transplantation

Acronym

AMADEUS

Study hypothesis

The aim of the study is to find out if there is a difference in the relapse free survival of patients with AML or high risk MDS treated with maintenance therapy of oral azacitidine versus placebo after stem cell transplantation.

Ethics approval

Approved 02/05/2019, East Midlands - Leicester Central Research Ethics Committee (The Old Chapel, Royal Standard Place, Nottingham, NG1 6FS; Tel: +44 (0)207 1048098; Email: nrescommittee.eastmidlands-leicestercentral@nhs.net), ref: 19/EM/0063

Study design

Randomised; Interventional; Design type: Treatment, Drug

Primary study design

Interventional

Secondary study design

Randomised controlled trial

Trial setting

Hospitals

Trial type

Treatment

Patient information sheet

Not available in web format, please use the contact details to request a patient information sheet

Condition

Acute myeloid leukaemia, myelodysplastic syndromes

Intervention

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 commence therapy between days 42 and 84 post-transplant up to a maximum of 12 months from the date of transplant. Patients will be followed up for 2 years for survival information.

Intervention type

Drug

Phase

Phase III

Drug names

Azacitidine (CC-486)

Primary outcome measure

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 outcome measures

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

Overall trial start date

07/07/2017

Overall trial end date

14/06/2024

Reason abandoned (if study stopped)

Eligibility

Participant inclusion criteria

1. Age > = 16 at the time of signing the informed consent form
2. Patients with a diagnosis of AML (CR1 or CR2) according to WHO classification or high risk MDS (as per IPSS-R) undergoing allo-SCT using MAC or RIC preparative regimens, and with either peripheral blood or bone marrow as the source of hematopoietic stem cells.
3. At the time of allo-SCT:
3.1. No prior allo-SCT; and
3.2. No more than 1 antigen mismatch at HLA-A, -B, -C, -DRB1 or -DQB1 locus for either related or unrelated donor; and
3.3. No haplotype or cord blood donor; and
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 10^9/L on two consecutive testing without daily use of myeloid growth factor; and
6.2. Platelet > = 50 x 10^9/L on two consecutive testing without platelet transfusion within 1 week
7. Adequate organ function:
7.1. Serum AST and 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 seconds, PTT < = 40 seconds, and/or INR < = 1.5)
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 (FCBP) 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) throughout the study, and for 3 months following the last dose of study therapy and
11.2. Have a negative serum pregnancy test (sensitivity of at least 25 mIU/mL) at screening; and
11.3. Have a negative serum or urine (investigator’s discretion) pregnancy test (sensitivity of at least 25 mIU/mL) within 72 hours 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 for study visits) and other protocol requirements

Participant type

Patient

Age group

Adult

Gender

Both

Target number of participants

Planned Sample Size: 324; UK Sample Size: 324

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 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
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. Prior history of/concurrent malignancies (including CMML). However, subjects with the following history/concurrent conditions are allowed:
9.1. Basal or squamous cell carcinoma of the skin
9.2. Carcinoma in situ of the cervix
9.3. Carcinoma in situ of the breast
9.4. Incidental histologic finding of prostate cancer (T1a or T1b using the tumor, node, metastasis (TNM) clinical staging system)
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

Recruitment start date

14/06/2019

Recruitment end date

14/06/2022

Locations

Countries of recruitment

United Kingdom

Trial participating centre

Beatson West of Scotland Cancer Centre
Glasgow
G12 0YN
United Kingdom

Trial participating centre

King's College Hospital
London
SE5 9RS
United Kingdom

Trial participating centre

St. James's University Hospital
Leeds
LS9 7TF
United Kingdom

Trial participating centre

Manchester Royal Infirmary
Manchester
M13 9WL
United Kingdom

Trial participating centre

Freeman Hospital
Newcastle-Upon-Tyne
NE7 7DN
United Kingdom

Trial participating centre

Churchill Hospital
Oxford
OX3 7LE
United Kingdom

Trial participating centre

Queen Elizabeth Hospital
Birmingham
B15 2TH
United Kingdom

Trial participating centre

St Bartholomew’s Hospital
London
EC1A 7BE
United Kingdom

Trial participating centre

Bristol Haematology and Oncology Centre
Bristol
BS2 8ED
United Kingdom

Trial participating centre

University College London Hospitals
London
NW1 2BU
United Kingdom

Trial participating centre

Addenbrookes Hospital
Cambridge
CB2 0QQ
United Kingdom

Trial participating centre

University Hospital of Wales
Cardiff
CF14 4XW
United Kingdom

Trial participating centre

Christie Hospital
Manchester
M20 4BX
United Kingdom

Trial participating centre

Hammersmith Hospital
London
W12 0HS
United Kingdom

Trial participating centre

Birmingham Heartlands Hospital
Birmingham
B9 5SS
United Kingdom

Trial participating centre

Leicester Royal Infirmary
Leicester
LE1 5WW
United Kingdom

Trial participating centre

The Clatterbridge Cancer Centre
Liverpool
CH63 4JY
United Kingdom

Trial participating centre

Nottingham City Hospital
Nottingham
NG5 1PB
United Kingdom

Trial participating centre

Derriford Hospital
Plymouth
PL6 8DH
United Kingdom

Trial participating centre

The Royal Marsden Hospital
London
SW3 6JJ
United Kingdom

Trial participating centre

Royal Hallamshire Hospital
Sheffield
S5 7AU
United Kingdom

Trial participating centre

Southampton General Hospital
Southampton
SO16 6YD
United Kingdom

Sponsor information

Organisation

University of Birmingham

Sponsor details

Research Support Group
Aston Webb Building
Edgbaston
Birmingham
B15 2TT
United Kingdom
+44 (0)121 371 7858
amadeus@trials.bham.ac.uk

Sponsor type

Hospital/treatment centre

Website

Funders

Funder type

Charity

Funder name

IMPACT (funded by NHS Blood & Transplant, Anthony Nolan and Leuka)

Alternative name(s)

Funding Body Type

Funding Body Subtype

Location

Funder name

Celgene

Alternative name(s)

Celgene Corporation

Funding Body Type

private sector organisation

Funding Body Subtype

For-profit companies (industry)

Location

United States of America

Results and Publications

Publication and dissemination plan

Planned publication in a high-impact peer reviewed journal in 2025.

IPD sharing statement
The data sharing plans for the current study are unknown and will be made available at a later date.

Intention to publish date

01/04/2025

Participant level data

To be made available at a later date

Basic results (scientific)

Publication list

Publication citations

Additional files

Editorial Notes

04/06/2020: Recruitment for this study is no longer paused. 20/04/2020: Due to current public health guidance, recruitment for this study has been paused. 18/03/2020: Link to plain English summary on CRUK added. 05/08/2019: Internal review. 08/07/2019: The funder name was updated from 'Leuka' to 'IMPACT (funded by NHS Blood & Transplant, Anthony Nolan and Leuka)'. 05/07/2019: Ethics approval information added. 21/06/2019: Internal review. 14/06/2019: The following changes were made to the trial record: 1. The recruitment start date was changed from 01/04/2019 to 14/06/2019. 2. The recruitment end date was changed from 01/04/2022 to 14/06/2022. 3. The overall trial end date was changed from 01/04/2024 to 14/06/2024. 05/04/2019: Internal review. 22/03/2019: The condition has been changed from "Specialty: Cancer, Primary sub-specialty: Haematological Oncology; Health Category: Cancer and neoplasms; Disease/Condition: Malignant neoplasms, stated or presumed to be primary, of lymphoid, haematopoietic and related tissue" to "Acute myeloid leukaemia, myelodysplastic syndromes" following a request from the NIHR.