Trial to Test the Effects of Adding 1 of 2 New Treatment Agents to Commonly Used Chemotherapy Combinations

Myelodysplastic Syndrome Clinical Trial

— AML18  

Official title:

A Trial for Older Patients With Acute Myeloid Leukaemia and High Risk Myelodysplastic Syndrome

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT02272478
• Other study ID #: AML18
• Status: Recruiting
• Phase: Phase 2/Phase 3
• 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
• 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.

Related Conditions & MeSH terms

• Acute Myeloid Leukaemia
• Leukemia
• Leukemia, Myeloid
• Leukemia, Myeloid, Acute
• Myelodysplastic Syndrome
• Myelodysplastic Syndromes
• Preleukemia

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