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Clinical Trial Details — Status: Recruiting

Administrative data

NCT number NCT02272478
Other study ID # AML18
Secondary ID
Status Recruiting
Phase Phase 2/Phase 3
First received
Last updated
Start date October 30, 2014
Est. completion date February 2022

Study information

Verified date August 2019
Source Cardiff University
Contact Sophie King
Phone 02922510527
Email aml18@cardiff.ac.uk
Is FDA regulated No
Health authority
Study type Interventional

Clinical Trial 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.


Description:

AML18 is a trial primarily for older patients with AML and high risk Myelodysplastic Syndrome (MDS). It offers a randomised controlled Phase II/III trial which uses a factorial design for maximum efficiency to evaluate two induction options followed by treatment with small molecule beyond course 1, and dose intensification for patients without evidence of MRD negativity.

There are five randomised comparisons within the trial:

1. At diagnosis:

For patients not known to have adverse risk cytogenetics DA chemotherapy plus a single dose of 3 mg/m2 of Mylotarg versus CPX-351. Patients with abnormal LFTs can enter the randomisation but receive DA alone or CPX-351.

2. For patients who received DA chemotherapy but are not in CR or who are MRD +ve, or for whom MRD is not assessable.

DA versus DAC versus FLAG-Ida

3. All patients at second course who have received DA and have not received Vosaroxin and Decitabine induction AC220 versus no AC220 for a maximum of 3 cycles; then with or without maintenance for 1 year for patients allocated AC220

4. For patients who are in CR or CRi and MRD -ve post course1 and have completed 2 courses of DA DA versus intermediate dose Cytarabine (IDAC)

5. For patients who received CPX-351 chemotherapy but are not in CR or who are MRD +ve, or for whom MRD is not assessable CPX-351 100 units/m2 x 3 doses versus CPX-351 100 units/m2 x 2 doses

The trial will also assess:

- Non-intensive allogeneic stem cell transplant for patients with matched sibling or matched unrelated donors.

- The combination of Vosaroxin and Decitabine for those with known adverse risk cytogenetics at diagnosis


Recruitment information / eligibility

Status Recruiting
Enrollment 1600
Est. completion date February 2022
Est. primary completion date February 2021
Accepts healthy volunteers No
Gender All
Age group 60 Years and older
Eligibility Inclusion Criteria

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

Exclusion criteria

Patients are not eligible for the AML18 trial if:

- They have previously received cytotoxic chemotherapy for AML [Hydroxycarbamide, or similar low-dose therapy, to control the white count prior to initiation of intensive therapy, is not an exclusion]

- 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

Specific exclusion criteria for the Mylotarg Arm

- 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

Specific exclusion criteria for the Vosaroxin/Decitabine Entry

- 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

- Left ventricular ejection fraction (LVEF) < 40% by multiple gated acquisition (MUGA) scan or echocardiogram (ECHO)]

Specific exclusion criteria for CPX-351 treatment

- Hypersensitivity to cytarabine, daunorubicin or liposomal products

- History of Wilson's disease or other copper-metabolism disorder

Specific exclusion criteria for Cladribine

• Patient's serum creatinine must be within the local ULN to enter the randomisation. Patients for whom this is not the case can be randomised between the remaining options.

In addition patients are not eligible for the AC220 randomisation if they have:

Cardiovascular System Exclusion Criteria:

Known serious cardiac illness or medical conditions, including but not limited to:

I. Clinically unstable cardiac disease, including unstable atrial fibrillation, symptomatic bradycardia, unstable congestive heart failure, active myocardial ischemia, or indwelling temporary pacemaker II. Ventricular tachycardia or a supraventricular tachycardia that requires treatment with a Class Ia antiarrhythmic drug (e.g., quinidine, procainamide, disopyramide) or Class III antiarrhythmic drug (e.g., sotalol, amiodarone, dofetilide). Use of other antiarrhythmic drugs is permitted.

III. Use of medications that have been linked to the occurrence of torsades de pointes (see Appendix for the list of such medications) IV. Second- or third-degree atrioventricular (AV) block unless treated with a permanent pacemaker V. Complete left bundle branch block (LBBB) VI. History of long QT Syndrome or a family member with this condition VII. Serum potassium, magnesium, and calcium levels not outside the laboratory's reference range VIII. QTc >450 ms (average of triplicate ECG recordings); a consistent method of QTc calculation must be used for each patient's QTc measurements. QTcF (Fridericia's formula) is preferred. Please see the trial website for QTcF calculator.

Study Design


Intervention

Drug:
Arm A Mylotarg plus DA Versus CPX-351
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.
Arm B Vosaroxin and Decitabine
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.
Arm D Small molecule or Not
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.
Arm C DA V FLAG-Ida V 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 1:1:1 fashion between DA, FLAG-Ida (or mini FLAG-Ida if 70 years or older) and DAC.
Arm E CPX-351 (200 V 300)
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).
Arm F DA V IDAC
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.

Locations

Country Name City State
Denmark 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
United Kingdom 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
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 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 Arrowe Park Hospital Wirral
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

Sponsors (2)

Lead Sponsor Collaborator
Cardiff University Cancer Research UK

Countries where clinical trial is conducted

Denmark,  United Kingdom, 

Outcome

Type Measure Description Time frame Safety issue
Primary Overall survival 1 year
Primary Complete remission (CR + CRi) achievement and reasons for failure (for induction questions) 1 month
Primary Duration of remission, relapse rates and deaths in first CR 1 month
Primary Toxicity, both haematological and non-haematological 1 month
Primary Supportive care requirements (and other aspects of health economics) 6 months
Secondary The relevance of the presence of a cytogenetic abnormality in the bone marrow of patients in morphological remission At study end
Secondary The relevance of molecular characteristics and response to treatment 1 month
Secondary To store diagnostic tissue for future research in the AML Tissue Bank 6 years
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