Clinical trial NCT02272478: Trial to Test the Effects of Adding 1 of 2 New Treatment Agents to Commonly Used Chemotherapy Combinations
Official title: A Trial for Older Patients With Acute Myeloid Leukaemia and High Risk Myelodysplastic Syndrome
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
PHASE3
Conditions: Acute Myeloid Leukaemia
Myelodysplastic Syndrome
Keywords: AML
MDS
Lead sponsor: Cardiff University
Sponsor class: OTHER
Collaborators: name: Cancer Research UK
First posted: 2014-10-23
Enrollment: 1600
Sex: ALL
Minimum age (years): 60
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: FACTORIAL
Primary purpose: TREATMENT

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.

Detailed 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

Eligibility criteria: 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.

Primary outcomes:
measure: Overall survival
timeFrame: 1 year
measure: Complete remission (CR + CRi) achievement and reasons for failure (for induction questions)
timeFrame: 1 month
measure: Duration of remission, relapse rates and deaths in first CR
timeFrame: 1 month
measure: Toxicity, both haematological and non-haematological
timeFrame: 1 month
measure: Supportive care requirements (and other aspects of health economics)
timeFrame: 6 months
Secondary outcomes:
measure: The relevance of the presence of a cytogenetic abnormality in the bone marrow of patients in morphological remission
timeFrame: At study end
measure: The relevance of molecular characteristics and response to treatment
timeFrame: 1 month
measure: To store diagnostic tissue for future research in the AML Tissue Bank
timeFrame: 6 years
Other outcomes:
Locations:
city: Aalborg
country: Denmark
facility: Aalborg University Hospital
city: Aarhus
country: Denmark
facility: Aarhus University Hospital
city: Copenhagen
country: Denmark
facility: Herlev and Gentofte Hospital
city: Copenhagen
country: Denmark
facility: Rigshospitalet
city: Odense
country: Denmark
facility: Odense University Hospital
city: Roskilde
country: Denmark
facility: Roskilde Hospital
city: Aberdeen
country: United Kingdom
facility: Aberdeen Royal Infirmary
city: Airdrie
country: United Kingdom
facility: Monklands Hospital
city: Bangor
country: United Kingdom
facility: Ysbyty Gwynedd Hospital
city: Bath
country: United Kingdom
facility: Royal United Hospital Bath
city: Belfast
country: United Kingdom
facility: Belfast City Hospital
city: Birmingham
country: United Kingdom
facility: Birmingham Heartland Hospital
city: Birmingham
country: United Kingdom
facility: Queen Elizabeth Hospital
city: Blackpool
country: United Kingdom
facility: Blackpool Victoria Hospital
city: Bodelwyddan
country: United Kingdom
facility: Ysbyty Glan Clwyd
city: Boston
country: United Kingdom
facility: Pilgrim Hospital
city: Bournemouth
country: United Kingdom
facility: Royal Bournemouth General Hospital
city: Bradford
country: United Kingdom
facility: Bradford Royal Infirmary
city: Bristol
country: United Kingdom
facility: Bristol Haematology & Oncology Centre
city: Cambridge
country: United Kingdom
facility: Addenbrooke's Hospital
city: Cardiff
country: United Kingdom
facility: UHW
city: Cardiff
country: United Kingdom
facility: University Hospital of Wales
city: Cheltenham
country: United Kingdom
facility: Cheltenham General Hospital
city: Chester
country: United Kingdom
facility: Countess of Chester Hospital
city: Chichester
country: United Kingdom
facility: St Richard's Hospital
city: Coventry
country: United Kingdom
facility: University Hospital of Coventry and Warwickshire
city: Derby
country: United Kingdom
facility: Derby Teaching Hospital
city: Dudley
country: United Kingdom
facility: Russell Hall
city: Dundee
country: United Kingdom
facility: Ninewells Hospital
city: Edinburgh
country: United Kingdom
facility: Western General Hospital
city: Exeter
country: United Kingdom
facility: Royal Devon & Exeter Hospital
city: Glasgow
country: United Kingdom
facility: Beatson West of Scotland Cancer Centre
city: Glasgow
country: United Kingdom
facility: Hairmyres Hospital
city: Glasgow
country: United Kingdom
facility: The New Victoria Hospital
city: Gloucester
country: United Kingdom
facility: Gloucestershire Royal Hospital
city: Hamstead
country: United Kingdom
facility: Royal Free Hospital
city: Inverness
country: United Kingdom
facility: Raigmore Hospital
city: Ipswich
country: United Kingdom
facility: Ipswich Hospital
city: Irvine
country: United Kingdom
facility: Crosshouse & Ayr Hospital
city: Kettering
country: United Kingdom
facility: Kettering General Hospital
city: Kirkcaldy
country: United Kingdom
facility: Victoria Hospital
city: Larbert
country: United Kingdom
facility: Forth Valley Royal Hospital
city: Leeds
country: United Kingdom
facility: St Jame's University Hospital
city: Leicester
country: United Kingdom
facility: Leicester Royal Infirmary
city: Lincoln
country: United Kingdom
facility: Lincoln County Hospital
city: Liverpool
country: United Kingdom
facility: Aintree University Hospital
city: Liverpool
country: United Kingdom
facility: The Royal Liverpool University Hospital
city: London
country: United Kingdom
facility: Guy's Hospital
city: London
country: United Kingdom
facility: St Bartholomew's Hospital
city: London
country: United Kingdom
facility: St George's Hospital
city: London
country: United Kingdom
facility: The Royal Marsden
city: London
country: United Kingdom
facility: University College London Hospital
city: Maidstone
country: United Kingdom
facility: Maidstone District General Hospital
city: Manchester
country: United Kingdom
facility: Manchester Royal Infirmary
city: Manchester
country: United Kingdom
facility: The Christie Hospital
city: Middlesbrough
country: United Kingdom
facility: The James Cook University Hospital
city: Milton Keynes
country: United Kingdom
facility: Milton Keynes
city: Newcastle
country: United Kingdom
facility: Freeman Hospital
city: Northampton
country: United Kingdom
facility: Northampton General Hospital
city: Norwich
country: United Kingdom
facility: Norfolk & Norwich University
city: Nottingham
country: United Kingdom
facility: Nottingham University Hospital
city: Oldham
country: United Kingdom
facility: Royal Oldham Hospital
city: Oxford
country: United Kingdom
facility: Churchill Hospital
city: Plymouth
country: United Kingdom
facility: Derriford Hospital
city: Portsmouth
country: United Kingdom
facility: Queen Alexandra Hospital
city: Prescot
country: United Kingdom
facility: Whiston Hospital & St Helens
city: Romford
country: United Kingdom
facility: Queen's Hospital
city: Salford
country: United Kingdom
facility: Salford Royal Hospital
city: Salisbury
country: United Kingdom
facility: Salisbury District Hospital
city: Slough
country: United Kingdom
facility: Wexham Park Hospital
city: Southampton
country: United Kingdom
facility: Southampton General Hospital
city: Stafford
country: United Kingdom
facility: Stafford Hospital
city: Stoke-on-Trent
country: United Kingdom
facility: University Hospital of Royal Stoke
city: Sunderland
country: United Kingdom
facility: Sunderland Royal Hospital
city: Sutton
country: United Kingdom
facility: St Helier Hospital
city: Swansea
country: United Kingdom
facility: Singleton Hospital
city: Torquay
country: United Kingdom
facility: Torbay District General Hospital
city: Truro
country: United Kingdom
facility: Royal Cornwall Hospital
city: Uxbridge
country: United Kingdom
facility: Hillingdon Hospital
city: Wakefield
country: United Kingdom
facility: Pinderfields Hospital
city: West Bromwich
country: United Kingdom
facility: Sandwell Hospital
city: Wirral
country: United Kingdom
facility: Arrowe Park Hospital
city: Wishaw
country: United Kingdom
facility: Wishaw General Hospital
city: Wolverhampton
country: United Kingdom
facility: New Cross Hospital
city: Worcester
country: United Kingdom
facility: Worcestershire Royal Hospital
city: Worthing
country: United Kingdom
facility: Worthing Hospital
city: York
country: United Kingdom
facility: York Hospital
Study officials:
affiliation: Nottingham University
name: Nigel Russell, Prof
role: PRINCIPAL_INVESTIGATOR
References: