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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT04173533
Recruitment Status : Recruiting
First Posted : November 22, 2019
Last Update Posted : November 25, 2019
Information provided by (Responsible Party):
University of Birmingham

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Acute Myeloid Leukemia Myelodysplasia Drug: Oral azacitidine Drug: Matched placebo Phase 3

Detailed Description:
This is a prospective, two arm, double-blind, phase III clinical trial in adult patients with acute myeloid leukaemia (AML) and myelodisplasia (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)).

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 324 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official 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
Actual Study Start Date : June 14, 2019
Estimated Primary Completion Date : June 2024
Estimated Study Completion Date : June 2024

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 Name: 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 Name: CC-486

Primary Outcome Measures :
  1. Relapse free survival (RFS) [ Time Frame: 12 months ]
    To determine RFS at one year from randomisation of oral azacitidine compared with placebo in patients undergoing allo-SCT for AML/MDS

Secondary Outcome Measures :
  1. Overall survival (OS) [ Time Frame: 12 and 24 months ]
    OS at one and two years from randomisation of oral azacitidine compared with placebo

  2. Cumulative incidence of relapse (CIR) [ Time Frame: 12 and 24 months ]
    CIR at one and two years after treatment comparing oral azacitidine with placebo

  3. Non-relapse mortality (NRM) [ Time Frame: Day 100 and 12 months ]
    NRM at 100 days and 12 months after treatment comparing oral azacitidine with placebo

  4. Incidence of acute and chronic GVHD [ Time Frame: 24 months ]
    Incidence of acute and chronic GVHD comparing oral azacitidine with placebo

  5. Time to early treatment discontinuation [ Time Frame: 24 months ]
    Time to early treatment discontinuation compairing oral azacitidine with placebo

  6. Safety (adverse events) [ Time Frame: 24 months ]
    Number of patients with adverse events on oral azacitidine compared with placebo

  7. Quality of Life (EORTC-QLQ-C30 and EQ-5D) [ Time Frame: 24 months ]
    QoL will be measured to compare oral azacitidine with placebo

  8. GVHD-free and relapse-free survival (GRFS) [ Time Frame: 12 and 24 months ]
    GRFS defined as time from date of randomisation to date of first event or death

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   16 Years and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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

    • 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:

    • 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 AST and 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 (PT ≤ 15 seconds and 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 3 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 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 Epstein-Barr Virus (EBV) reactivation)
    • 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), CMML or Secondary AML arising from MDS. 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT04173533

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Contact: Eszter Nagy 00442123717858

Show Show 21 study locations
Sponsors and Collaborators
University of Birmingham
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Principal Investigator: Charles Craddock University of Birmingham

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Responsible Party: University of Birmingham Identifier: NCT04173533    
Other Study ID Numbers: RG_18-048
First Posted: November 22, 2019    Key Record Dates
Last Update Posted: November 25, 2019
Last Verified: October 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Leukemia, Myeloid
Leukemia, Myeloid, Acute
Myelodysplastic Syndromes
Neoplasms by Histologic Type
Bone Marrow Diseases
Hematologic Diseases
Precancerous Conditions
Antimetabolites, Antineoplastic
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Enzyme Inhibitors