Clinical Trials /

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

NCT04173533

Description:

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.

Related Conditions:
  • Acute Myeloid Leukemia
  • Myelodysplastic Syndromes
Recruiting Status:

Recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

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

Clinical Trial IDs

  • ORG STUDY ID: RG_18-048
  • NCT ID: NCT04173533

Conditions

  • Acute Myeloid Leukemia
  • Myelodysplasia

Interventions

DrugSynonymsArms
Oral azacitidineCC-486Experimental Group
Matched placeboOral azacitidine matched placeboControl Group

Purpose

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.

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)).
    

Trial Arms

NameTypeDescriptionInterventions
Control GroupPlacebo ComparatorOral azacitidine (CC-486) matched placebo once daily for first 14 days of each 28 day cycle
  • Matched placebo
Experimental GroupExperimentalOral azacitidine (CC-486) 200 mg once daily for first 14 days of each 28 day cycle
  • Oral azacitidine

Eligibility Criteria

        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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:16 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Relapse free survival (RFS)
Time Frame:12 months
Safety Issue:
Description: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

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

Details

Phase:Phase 3
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:University of Birmingham

Last Updated

November 22, 2019