Trial to Test the Effects of Adding 1 of 2 New Treatment Agents to Commonly Used Chemotherapy Combinations
AML18
A Trial for Older Patients With Acute Myeloid Leukaemia and High Risk Myelodysplastic Syndrome
1 other identifier
interventional
1,600
2 countries
87
Brief Summary
The AML18 Trial will evaluate several relevant therapeutic questions in Acute Myeloid Leukaemia (AML), as defined by the WHO, and High Risk Myelodysplastic Syndrome. The trial is primarily designed for patients over 60 years considered fit for an intensive chemotherapeutic approach, but younger patients who may not be considered suitable for the concurrent NCRI AML Trial for younger patients may also enter. Patients for whom intensive chemotherapy is not thought suitable may enter the concurrent NCRI trial of less intensive therapy (LI1). Approximately 1600 patients will be recruited. At entry, a randomisation will compare a standard chemotherapy schedule DA (Daunorubicin/Ara-C) combined with 1 dose of Mylotarg (gemtuzumab ozogamicin, or GO) in course 1 against CPX-351. Patients who have known adverse risk cytogenetics (using Grimwade 2010 classification favourable/intermediate/adverse) at diagnosis may enter a Phase 2 evaluation of the combination of Vosaroxin plus Decitabine. Patients who achieve complete remission (CR) and who are MRD negative by flow cytometry after course one of DA will receive one further course of DA, with a randomisation to receive, either a course of DA or intermediate dose Cytarabine (IDAC) as a third course. Patients who are MRD negative by flow cytometry after course one of CPX-351 will receive up to 2 further course of CPX. Patients who fail to achieve a CR after course 1 of DA or who are MRD positive by flow cytometry or for whom MRD information is not available, are eligible to be randomised to compare DA with DA plus Cladribine (DAC) or FLAG-Ida for up to two courses of therapy. Patients who fail to achieve a CR after course 1 of CPX-351 or who are MRD positive by flow cytometry or for whom MRD information is not available are eligible to be randomised between a second course of standard dose CPX versus a repeat of the course 1 schedule. Patients receiving Vosaroxin and Decitabine are excluded from these post course 1 randomisations . Following the outcome of course 1, patients who received DA chemotherapy on course 1 will be randomised to receive further chemotherapy with the 2nd generation FLT3 inhibitor AC220. Patients randomised to AC220 will be allocated a maximum of 3 courses (short AC220) or 3 courses plus maintenance for 1 year (long AC220). Patients receiving Vosaroxin and Decitabine are excluded from this randomisation. Patients will be eligible for a non-intensive allogeneic stem cell transplant if a suitable HLA matched donor is available.
Trial Health
Trial Health Score
Automated assessment based on enrollment pace, timeline, and geographic reach
participants targeted
Target at P75+ for phase_2
Started Oct 2014
Longer than P75 for phase_2
87 active sites
Health score is calculated from publicly available data and should be used for screening purposes only.
Trial Relationships
Click on a node to explore related trials.
Study Timeline
Key milestones and dates
First Submitted
Initial submission to the registry
June 10, 2014
CompletedFirst Posted
Study publicly available on registry
October 23, 2014
CompletedStudy Start
First participant enrolled
October 30, 2014
CompletedPrimary Completion
Last participant's last visit for primary outcome
February 1, 2021
CompletedStudy Completion
Last participant's last visit for all outcomes
February 1, 2022
CompletedJanuary 23, 2020
August 1, 2019
6.3 years
June 10, 2014
January 22, 2020
Conditions
Keywords
Outcome Measures
Primary Outcomes (5)
Overall survival
1 year
Complete remission (CR + CRi) achievement and reasons for failure (for induction questions)
1 month
Duration of remission, relapse rates and deaths in first CR
1 month
Toxicity, both haematological and non-haematological
1 month
Supportive care requirements (and other aspects of health economics)
6 months
Secondary Outcomes (3)
The relevance of the presence of a cytogenetic abnormality in the bone marrow of patients in morphological remission
At study end
The relevance of molecular characteristics and response to treatment
1 month
To store diagnostic tissue for future research in the AML Tissue Bank
6 years
Study Arms (6)
Arm A
ACTIVE COMPARATORPatients not known adverse karyotype Randomise between Daunorubicin 60mg/m2 daily by i.v. infusion on days 1, 3 and 5 (3 doses) Cytosine Arabinoside 100mg/m2 12 hourly by i.v. push on days 1 - 10 inclusive (20 doses) Mylotarg (GO) 3mg/m2 on day 1 of DA chemotherapy Versus CPX-351 100 units/m2 on days 1, 3 and 5
Arm B
ACTIVE COMPARATORPatients with known adverse karyotype 5 cycles of Vosaroxin and Decitabine therapy
Arm C
ACTIVE COMPARATORPrior to Course 2 - Patients receving DA plus GO in course 1 and MRD positive PC1 Randomise between Daunorubicin 50mg/2 daily by i.v. infusion on days 1, 3 and 5 (3 doses) Cytosine Arabinoside 100mg/m2 12 hourly by i.v.push on days 1 - 8 inclusive (16 doses) Versus Daunorubicin 50mg/m2 daily by i.v. infusion on days 1, 3 and 5 Cytosine Arabinoside 100mg/m2 12 hourly by i.v. push on days 1 - 8 inclusive Cladribine 5mg/m2 daily on days 1 - 5 inclusive Versus Patients aged 60-69 Fludarabine 30mg/m2 daily on i.v. on days 2 - 6 inclusive Cytosine Arabinoside 1g/m2 daily over 4 hours Fludarabine on days 2 - 6 inclusive Patients aged 70+ Fludarabine 25mg/m2 daily i.v. on days 2 - 5 inclusive Cytosine Arabinoside 1g/m2 daily over 4 hours Fludarabine on days 2 - 5 inclusive Idarubicin 5mg/m2 i.v. daily on days 3, 4 and 5 (3 doses) And Randomisation to receive AC220 or not
Arm D
ACTIVE COMPARATORPrior to Course 2 - Patients that received DA plus GO in course 1 and MRD negative PC1 Randomisation to receive AC220 or not
Arm E
ACTIVE COMPARATORPrior to Course 2 for patients receiving CPX in course 1 and MRD positive PC1 Randomisation between CPX-351 100 units/m2 on days 1, and 3 (CPX 200) versus CPX-351 100 units/m2 on days 1, 3 and 5 (CPX 300)
Arm F
ACTIVE COMPARATORPrior to Course 3 - Patients that received DA plus GO in course 1 and MRD negative PC1 Randomise between Daunorubicin 50 mg/m2 daily by i.v. infusion on days 1 and 3 (2 doses) Cytosine Arabinoside 100 mg/m2 12-hourly by i.v. push on days 1 - 5 inclusive (10 doses) versus Intermediate dose Cytarabine (IDAC) schedule Cytosine Arabinoside 1g/m2 daily by 4 hour infusion on days 1- 5 inclusive (5 doses)
Interventions
Patients not known to have adverse risk cytogenetics will enter a randomisation comparing DA with Mylotarg (GO) delivered at 3mg/m2 on day 1 of chemotherapy, with CPX-351 on days 1, 3 and 5.
If a patient is known to have adverse risk Cytogenetics at diagnosis they will enter a registration to receive up to 5 courses of Vosaroxin and Decitabine.
The randomisation to AC220 or not will take place immediately before course 2 of treatment for patients who have received DA induction +/- Mylotarg, irrespective of residual disease status. Patients allocated to receive AC220 will be randomised in a 1:1 fashion to AC220 or no small molecule with a 1:1 randomisation in patients drawing AC220 between short and long therapy.
If a patient is not in CR or CRi after course 1 or is MRD +ve/unknown by flow cytometry they will be eligible to be randomised in a 1:1:1 fashion between DA, FLAG-Ida (or mini FLAG-Ida if 70 years or older) and DAC.
If a patient is not in CR or CRi after course 1 or is MRD +ve/unknown by flow cytometry they will be eligible to be randomised in a 1:1 fashion between CPX given on days 1, 3 and 5 (3 doses) and CPX given on days 1 and 3 (2 doses).
Following recovery from course 2, patients in the MRD-ve arm will be randomised between a further 5-day cycle of DA or a cycle of intermediate dose cytarabine (IDAC) as the third chemotherapy course.
Eligibility Criteria
You may qualify if:
- Patients are eligible for the AML18 trial if:
- They have one of the forms of acute myeloid leukaemia, except Acute Promyelocytic Leukaemia as defined by the WHO Classification (Appendix A) this can be any type of de novo or secondary AML - or high risk Myelodysplastic Syndrome, defined as greater than 10% marrow blasts (RAEB-2). (NB patients with prior MDS (\>10% blasts, RAEB2) have received azacitidine are not eligible for the trial, but patients with \<10% who have failed a hypomethylating agent and developed AML may enter the trial).
- Patients should normally be over the age of 60, but patients under this age are eligible if they are not considered eligible for the MRC AML19 trial please contact the trial team for further information.
- Patients entering the Vosaroxin/Decitabine arm must be over the age of 60 and have known adverse risk cytogenetics.
- They have given written informed consent.
- Serum creatinine ≤ 1.5 × ULN (upper limit of normal)
- Sexually mature males must agree to use an adequate and medically accepted method of contraception throughout the study if their sexual partners are women of child bearing potential (WOCBP). Men should be advised to not father a child while receiving trial treatment. Similarly women must agree to adequate contraceptive measures and avoid becoming pregnant while on protocol treatment. In both males and females these measures must be in place for at least 3 months following completion of Decitabine and at least 6 months after the last administration of Cladribine. The time period following treatment with Decitabine where it is safe to become pregnant is unknown. In the event of pregnancy at any point during the trial, the IMPs should be immediately stopped and the Trial Team should be contacted and pregnancy reporting procedures followed.
- ECOG Performance Status of 0-2
You may not qualify if:
- Patients are not eligible for the AML18 trial if:
- They are in blast transformation of chronic myeloid leukaemia (CML)
- They have a concurrent active malignancy excluding basal cell carcinoma
- They are pregnant or lactating
- They have Acute Promyelocytic Leukaemia
- Known infection with human immunodeficiency virus (HIV)
- Patients with prior cumulative anthracycline exposure (from prior treatment of a non AML cancer) of greater than 300 mg/m2 daunorubicin (or equivalent).
- History of myocardial infarction (MI), unstable angina, cerebrovascular accident, or transient ischemic attack (CVA/TIA) within 3 months before entry
- Pre-existing liver impairment with known cirrhosis
- Total bilirubin \> 1.5 x the upper limit of normal (ULN)
- Aspartate aminotransferase (AST) \> 2.5 x ULN
- Alanine aminotransferase (ALT) \> 2.5 x ULN
- Total bilirubin \> 1.5 x the upper limit of normal (ULN),
- Aspartate aminotransferase (AST) \> 2.5 x ULN
- Alanine aminotransferase (ALT) \> 2.5 x ULN
- +8 more criteria
Contact the study team to confirm eligibility.
Sponsors & Collaborators
- Cardiff Universitylead
- Cancer Research UKcollaborator
Study Sites (87)
Aalborg University Hospital
Aalborg, Denmark
Aarhus University Hospital
Aarhus, Denmark
Herlev and Gentofte Hospital
Copenhagen, Denmark
Rigshospitalet
Copenhagen, Denmark
Odense University Hospital
Odense, Denmark
Roskilde Hospital
Roskilde, Denmark
Aberdeen Royal Infirmary
Aberdeen, United Kingdom
Monklands Hospital
Airdrie, United Kingdom
Ysbyty Gwynedd Hospital
Bangor, United Kingdom
Royal United Hospital Bath
Bath, United Kingdom
Belfast City Hospital
Belfast, United Kingdom
Birmingham Heartland Hospital
Birmingham, United Kingdom
Queen Elizabeth Hospital
Birmingham, United Kingdom
Blackpool Victoria Hospital
Blackpool, United Kingdom
Ysbyty Glan Clwyd
Bodelwyddan, United Kingdom
Pilgrim Hospital
Boston, United Kingdom
Royal Bournemouth General Hospital
Bournemouth, United Kingdom
Bradford Royal Infirmary
Bradford, United Kingdom
Bristol Haematology & Oncology Centre
Bristol, United Kingdom
Addenbrooke's Hospital
Cambridge, United Kingdom
UHW
Cardiff, CF14 4XN, United Kingdom
University Hospital of Wales
Cardiff, United Kingdom
Cheltenham General Hospital
Cheltenham, United Kingdom
Countess of Chester Hospital
Chester, United Kingdom
St Richard's Hospital
Chichester, United Kingdom
University Hospital of Coventry and Warwickshire
Coventry, United Kingdom
Derby Teaching Hospital
Derby, United Kingdom
Russell Hall
Dudley, United Kingdom
Ninewells Hospital
Dundee, United Kingdom
Western General Hospital
Edinburgh, United Kingdom
Royal Devon & Exeter Hospital
Exeter, United Kingdom
Beatson West of Scotland Cancer Centre
Glasgow, United Kingdom
Hairmyres Hospital
Glasgow, United Kingdom
The New Victoria Hospital
Glasgow, United Kingdom
Gloucestershire Royal Hospital
Gloucester, United Kingdom
Royal Free Hospital
Hamstead, United Kingdom
Raigmore Hospital
Inverness, United Kingdom
Ipswich Hospital
Ipswich, United Kingdom
Crosshouse & Ayr Hospital
Irvine, United Kingdom
Kettering General Hospital
Kettering, United Kingdom
Victoria Hospital
Kirkcaldy, United Kingdom
Forth Valley Royal Hospital
Larbert, United Kingdom
St Jame's University Hospital
Leeds, United Kingdom
Leicester Royal Infirmary
Leicester, United Kingdom
Lincoln County Hospital
Lincoln, United Kingdom
Aintree University Hospital
Liverpool, United Kingdom
The Royal Liverpool University Hospital
Liverpool, United Kingdom
Guy's Hospital
London, United Kingdom
St Bartholomew's Hospital
London, United Kingdom
St George's Hospital
London, United Kingdom
The Royal Marsden
London, United Kingdom
University College London Hospital
London, United Kingdom
Maidstone District General Hospital
Maidstone, United Kingdom
Manchester Royal Infirmary
Manchester, United Kingdom
The Christie Hospital
Manchester, United Kingdom
Arrowe Park Hospital
Metropolitan Borough of Wirral, United Kingdom
The James Cook University Hospital
Middlesbrough, United Kingdom
Milton Keynes
Milton Keynes, United Kingdom
Freeman Hospital
Newcastle, United Kingdom
Northampton General Hospital
Northampton, United Kingdom
Norfolk & Norwich University
Norwich, United Kingdom
Nottingham University Hospital
Nottingham, United Kingdom
Royal Oldham Hospital
Oldham, United Kingdom
Churchill Hospital
Oxford, United Kingdom
Derriford Hospital
Plymouth, United Kingdom
Queen Alexandra Hospital
Portsmouth, United Kingdom
Whiston Hospital & St Helens
Prescot, United Kingdom
Queen's Hospital
Romford, United Kingdom
Salford Royal Hospital
Salford, United Kingdom
Salisbury District Hospital
Salisbury, United Kingdom
Wexham Park Hospital
Slough, United Kingdom
Southampton General Hospital
Southampton, United Kingdom
Stafford Hospital
Stafford, United Kingdom
University Hospital of Royal Stoke
Stoke-on-Trent, United Kingdom
Sunderland Royal Hospital
Sunderland, United Kingdom
St Helier Hospital
Sutton, United Kingdom
Singleton Hospital
Swansea, United Kingdom
Torbay District General Hospital
Torquay, United Kingdom
Royal Cornwall Hospital
Truro, United Kingdom
Hillingdon Hospital
Uxbridge, United Kingdom
Pinderfields Hospital
Wakefield, United Kingdom
Sandwell Hospital
West Bromwich, United Kingdom
Wishaw General Hospital
Wishaw, United Kingdom
New Cross Hospital
Wolverhampton, United Kingdom
Worcestershire Royal Hospital
Worcester, United Kingdom
Worthing Hospital
Worthing, United Kingdom
York Hospital
York, United Kingdom
MeSH Terms
Conditions
Interventions
Condition Hierarchy (Ancestors)
Intervention Hierarchy (Ancestors)
Study Officials
- PRINCIPAL INVESTIGATOR
Nigel Russell, Prof
Nottingham University
Central Study Contacts
Study Design
- Study Type
- interventional
- Phase
- phase 2
- Allocation
- RANDOMIZED
- Masking
- NONE
- Purpose
- TREATMENT
- Intervention Model
- FACTORIAL
- Sponsor Type
- OTHER
- Responsible Party
- PRINCIPAL INVESTIGATOR
- PI Title
- Prof
Study Record Dates
First Submitted
June 10, 2014
First Posted
October 23, 2014
Study Start
October 30, 2014
Primary Completion
February 1, 2021
Study Completion
February 1, 2022
Last Updated
January 23, 2020
Record last verified: 2019-08