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

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

This study will evaluate a new maintenance therapy with the aim of improving the outcome of patients with acute myeloid leukaemia (AML) and myelodysplasia (MDS) after stem cell transplantation.

Study Overview

• Status: Recruiting
• Conditions: Acute Myeloid Leukemia; Myelodysplasia
• Intervention / Treatment: Drug: Matched placebo; Drug: Oral azacitidine

Detailed Description

This is a prospective, two arm, double-blind, phase III clinical trial in adult patients with acute myeloid leukaemia (AML) and myelodysplasia (MDS) who have undergone an allogeneic stem cell transplant (allo-SCT) and are randomised to receive oral azacitidine or placebo upon engraftment for up to 12 months as maintenance therapy. Patients will be stratified by type of transplant (myeloablative/reduced intensity, age (<60/≥ 60 years) and donor type (sibling/unrelated)).

• Study Type: Interventional
• Enrollment (Anticipated): 324
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Rebecca Collings; Phone Number: 0121 371 7868; Email: amadeus@trials.bham.ac.uk

Study Locations

• United Kingdom
  • Birmingham, United Kingdom
    • Recruiting
    • The Queen Elizabeth Hospital
    • Principal Investigator: Charles Craddock
  • Bristol, United Kingdom
    • Recruiting
    • University Hospital Bristol
    • Principal Investigator: Rachel Protheroe
  • Cambridge, United Kingdom
    • Recruiting
    • Addenbrooke's Hospital
    • Principal Investigator: Charles Crawley
  • Cardiff, United Kingdom
    • Recruiting
    • University Hospital of Wales
    • Principal Investigator: Wendy Ingram
  • Glasgow, United Kingdom
    • Recruiting
    • Queen Elizabeth University Hospital
  • Leeds, United Kingdom
    • Recruiting
    • St. James's University Hospital
    • Principal Investigator: Maria Gilleece
  • Leicester, United Kingdom
    • Recruiting
    • Leicester Royal Infirmary
    • Principal Investigator: Alexander M Martin
  • Liverpool, United Kingdom
    • Recruiting
    • Clatterbridge Cancer Centre
  • London, United Kingdom
    • Recruiting
    • King's College Hospital
    • Principal Investigator: Victoria Potter
  • London, United Kingdom
    • Recruiting
    • Hammersmith Hospital
  • London, United Kingdom
    • Recruiting
    • The Royal Marsden Hospital
    • Principal Investigator: Sandra Easdale
  • London, United Kingdom
    • Recruiting
    • University College London Hospitals
    • Principal Investigator: Panagiotis Kottaridis
  • London, United Kingdom
    • Recruiting
    • St Bartholomew's Hospital
    • Principal Investigator: Jeff Davies
  • Manchester, United Kingdom
    • Recruiting
    • Manchester Royal Infirmary
    • Principal Investigator: Fiona Dignan
  • Manchester, United Kingdom
    • Recruiting
    • The Christie Hospital
    • Principal Investigator: Mike Dennis
  • Newcastle, United Kingdom
    • Recruiting
    • Freeman Hospital
    • Principal Investigator: Erin Hurst
  • Nottingham, United Kingdom
    • Recruiting
    • Nottingham City Hospital
    • Principal Investigator: Jenny Byrne
  • Oxford, United Kingdom
    • Recruiting
    • Churchill Hospital
    • Principal Investigator: Andy Peniket
  • Plymouth, United Kingdom
    • Recruiting
    • Derriford Hospital
    • Principal Investigator: Hannah Hunter
  • Sheffield, United Kingdom
    • Recruiting
    • Royal Hallamshire Hospital
    • Principal Investigator: Harpreet Kaur

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (ADULT, OLDER_ADULT, CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 hematological disease 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-intensity conditioning (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

   • No prior allo-SCT; and
   • No more than 1 antigen mismatch at HLA-A, -B, -C, -DRB1 or -DQB1 locus for either 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

   1. AML patients - blast count ≤ 5% confirmed within 28 days prior to starting study therapy
   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:

   • Absolute neutrophil count (ANC) ≥ 1.0 x 10^9/L on two consecutive testing without daily use of myeloid growth factor; and
   • Platelet ≥ 50 x 10^9/L on two consecutive testing without platelet transfusion within 1 week

7. Adequate organ function:

   • Serum aspartate aminotransferase (AST) and alanine transaminase (ALT) < 4 x upper limit of normal (ULN)
   • 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
   • Serum creatinine < 2 x ULN
8. Adequate coagulation (Prothrombin time (PT) ≤ 15 seconds and partial thromboplastin time (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 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:

    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 6 months following the last dose of study therapy and
    2. Have a negative serum pregnancy test (sensitivity of at least 25 mIU/mL) at screening; and
    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 from 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

Exclusion Criteria:

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

   • Any chemotherapy used for adjuvant therapy
   • Unlicensed investigational agents/therapies used within 28 days prior to starting study therapy
   • Azacitidine, decitabine or other hypomethylating agent (HMA)
   • 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. History of prior malignancies, except: lobular breast carcinoma in situ, fully resected basal cell or squamous cell carcinoma of skin or treated cervical carcinoma in situ, Incidental histologic finding of prostate cancer (T1a or T1b using the tumor, node, metastasis (TNM) clinical staging system), previous MDS, CMML, myeloproliferative neoplasms (MPN) resulting in secondary AML. Cancer treated with curative intent ≥ 5 years previously will be allowed. Cancer treated with curative intent < 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 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: DOUBLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
PLACEBO_COMPARATOR: Control Group; Oral azacitidine (CC-486) matched placebo once daily for first 14 days of each 28 day cycle	Drug: Matched placebo; Oral azacitidine (CC-486) matched placebo tablet; Other Names: Oral azacitidine matched placebo
EXPERIMENTAL: Experimental Group; Oral azacitidine (CC-486) 200 mg once daily for first 14 days of each 28 day cycle	Drug: Oral azacitidine; Oral azacitidine (CC-486) 200 mg tablet; Other Names: CC-486

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Relapse free survival (RFS)	To determine RFS at one year from randomisation of oral azacitidine compared with placebo in patients undergoing allo-SCT for AML/MDS	12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall survival (OS)	OS at one and two years from randomisation of oral azacitidine compared with placebo	12 and 24 months
Cumulative incidence of relapse (CIR)	CIR at one and two years after treatment comparing oral azacitidine with placebo	12 and 24 months
Non-relapse mortality (NRM)	NRM at 100 days and 12 months after treatment comparing oral azacitidine with placebo	Day 100 and 12 months
Incidence of acute and chronic graft-versus-host disease (GVHD)	Incidence of acute and chronic GVHD comparing oral azacitidine with placebo	24 months
Time to early treatment discontinuation	Time to early treatment discontinuation comparing oral azacitidine with placebo	24 months
Safety (adverse events)	Number of patients with adverse events on oral azacitidine compared with placebo	24 months
Quality of Life (EORTC-QLQ-C30 and EQ-5D)	QoL will be measured to compare oral azacitidine with placebo	24 months
GVHD-free and relapse-free survival (GRFS)	GRFS defined as time from date of randomisation to date of first event or death	12 and 24 months

Collaborators and Investigators

• Sponsor: University of Birmingham
• Investigators: Principal Investigator: Charles Craddock, University of Birmingham

Study record dates

Study Major Dates

• Study Start (ACTUAL): June 14, 2019
• Primary Completion (ANTICIPATED): April 1, 2024
• Study Completion (ANTICIPATED): April 1, 2025

Study Registration Dates

• First Submitted: November 20, 2019
• First Submitted That Met QC Criteria: November 20, 2019
• First Posted (ACTUAL): November 22, 2019

Study Record Updates

• Last Update Posted (ACTUAL): November 3, 2022
• Last Update Submitted That Met QC Criteria: November 2, 2022
• Last Verified: November 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Bone Marrow Diseases; Hematologic Diseases; Precancerous Conditions; Myelodysplastic Syndromes; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Preleukemia; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Azacitidine
• Other Study ID Numbers: RG_18-048

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No