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

Acute Myeloid Leukemia Clinical Trial

— AMADEUS  

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 Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT04173533
• Other study ID #: RG_18-048
• Status: Active, not recruiting
• Phase: Phase 3
• Start date: June 14, 2019
• Est. completion date: April 2025

Study information

• Verified date: May 2024
• Source: University of Birmingham
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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)).

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 326
• Est. completion date: April 2025
• Est. primary completion date: April 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 16 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Acute Myeloid Leukemia
• Leukemia
• Leukemia, Myeloid
• Leukemia, Myeloid, Acute
• Myelodysplasia
• Myelodysplastic Syndromes
• Preleukemia

Intervention

Drug:
• Oral azacitidine
Oral azacitidine (CC-486) 200 mg tablet
• Matched placebo
Oral azacitidine (CC-486) matched placebo tablet

Locations

Country	Name	City	State
United Kingdom	The Queen Elizabeth Hospital	Birmingham
United Kingdom	University Hospital Bristol	Bristol
United Kingdom	Addenbrooke's Hospital	Cambridge
United Kingdom	University Hospital of Wales	Cardiff
United Kingdom	Queen Elizabeth University Hospital	Glasgow
United Kingdom	St. James's University Hospital	Leeds
United Kingdom	Leicester Royal Infirmary	Leicester
United Kingdom	Clatterbridge Cancer Centre	Liverpool
United Kingdom	Hammersmith Hospital	London
United Kingdom	King's College Hospital	London
United Kingdom	St Bartholomew's Hospital	London
United Kingdom	The Royal Marsden Hospital	London
United Kingdom	University College London Hospitals	London
United Kingdom	Manchester Royal Infirmary	Manchester
United Kingdom	The Christie Hospital	Manchester
United Kingdom	Freeman Hospital	Newcastle
United Kingdom	Nottingham City Hospital	Nottingham
United Kingdom	Churchill Hospital	Oxford
United Kingdom	Derriford Hospital	Plymouth
United Kingdom	Royal Hallamshire Hospital	Sheffield

Sponsors (1)

Lead Sponsor	Collaborator
University of Birmingham

Country where clinical trial is conducted

United Kingdom, 

Outcome

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