Clinical trial NCT04173533: 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
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Acute Myeloid Leukemia
Myelodysplasia
Lead sponsor: University of Birmingham
Sponsor class: OTHER
First posted: 2019-11-22
Enrollment: 326
Sex: ALL
Minimum age (years): 16
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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)).

Eligibility criteria: 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

Primary outcomes:
measure: Relapse free survival (RFS)
timeFrame: 12 months
Secondary outcomes:
measure: Overall survival (OS)
timeFrame: 12 and 24 months
measure: Cumulative incidence of relapse (CIR)
timeFrame: 12 and 24 months
measure: Non-relapse mortality (NRM)
timeFrame: Day 100 and 12 months
measure: Incidence of acute and chronic graft-versus-host disease (GVHD)
timeFrame: 24 months
measure: Time to early treatment discontinuation
timeFrame: 24 months
measure: Safety (adverse events)
timeFrame: 24 months
measure: Quality of Life (EORTC-QLQ-C30 and EQ-5D)
timeFrame: 24 months
measure: GVHD-free and relapse-free survival (GRFS)
timeFrame: 12 and 24 months
Other outcomes:
Locations:
city: Birmingham
country: United Kingdom
facility: The Queen Elizabeth Hospital
city: Bristol
country: United Kingdom
facility: University Hospital Bristol
city: Cambridge
country: United Kingdom
facility: Addenbrooke's Hospital
city: Cardiff
country: United Kingdom
facility: University Hospital of Wales
city: Glasgow
country: United Kingdom
facility: Queen Elizabeth University Hospital
city: Leeds
country: United Kingdom
facility: St. James's University Hospital
city: Leicester
country: United Kingdom
facility: Leicester Royal Infirmary
city: Liverpool
country: United Kingdom
facility: Clatterbridge Cancer Centre
city: London
country: United Kingdom
facility: Hammersmith Hospital
city: London
country: United Kingdom
facility: King's College Hospital
city: London
country: United Kingdom
facility: St Bartholomew's Hospital
city: London
country: United Kingdom
facility: The Royal Marsden Hospital
city: London
country: United Kingdom
facility: University College London Hospitals
city: Manchester
country: United Kingdom
facility: Manchester Royal Infirmary
city: Manchester
country: United Kingdom
facility: The Christie Hospital
city: Newcastle
country: United Kingdom
facility: Freeman Hospital
city: Nottingham
country: United Kingdom
facility: Nottingham City Hospital
city: Oxford
country: United Kingdom
facility: Churchill Hospital
city: Plymouth
country: United Kingdom
facility: Derriford Hospital
city: Sheffield
country: United Kingdom
facility: Royal Hallamshire Hospital
Study officials:
affiliation: University of Birmingham
name: Charles Craddock
role: PRINCIPAL_INVESTIGATOR
References: