AML18: Trial to Test the Effects of Adding 1 of 2 New Treatment Agents to Commonly Used Chemotherapy Combinations

Sponsor

Cardiff University (Other)

Overall Status

Unknown status

CT.gov ID

NCT02272478

Collaborator

Cancer Research UK (Other)

1,600

Enrollment

Locations

Arms

87.1

Anticipated Duration (Months)

18.4

Patients Per Site

0.2

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Acute Myeloid Leukaemia Myelodysplastic Syndrome	Drug: Arm A Mylotarg plus DA Versus CPX-351 Drug: Arm B Vosaroxin and Decitabine Drug: Arm D Small molecule or Not Drug: Arm C DA V FLAG-Ida V DAC Drug: Arm E CPX-351 (200 V 300) Drug: Arm F DA V IDAC	Phase 2/Phase 3

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:

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.

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

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
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)
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

Study Design

Study Type:

Interventional

Anticipated Enrollment :

1600 participants

Allocation:

Randomized

Intervention Model:

Factorial Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Oct 30, 2014

Anticipated Primary Completion Date :

Feb 1, 2021

Anticipated Study Completion Date :

Feb 1, 2022

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Arm A Patients 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	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. Other Names: Mylotarg (GO) CPX-351
Active Comparator: Arm B Patients with known adverse karyotype 5 cycles of Vosaroxin and Decitabine therapy	Drug: 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. Other Names: Vosaroxin Decitabine
Active Comparator: Arm C Prior 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	Drug: 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. Other Names: No AC220 Drug: 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. Other Names: DA FLAG-Ida DAC
Active Comparator: Arm D Prior to Course 2 - Patients that received DA plus GO in course 1 and MRD negative PC1 Randomisation to receive AC220 or not	Drug: 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. Other Names: No AC220
Active Comparator: Arm E Prior 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)	Drug: 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). Other Names: CPX-351
Active Comparator: Arm F Prior 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)	Drug: 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. Other Names: IDAC DA

Outcome Measures

Primary Outcome Measures

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 Outcome Measures

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]

Eligibility Criteria

Criteria

Ages Eligible for Study:

60 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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:

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.
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.

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	Aalborg University Hospital	Aalborg	Denmark
2	Aarhus University Hospital	Aarhus	Denmark
3	Herlev and Gentofte Hospital	Copenhagen	Denmark
4	Rigshospitalet	Copenhagen	Denmark
5	Odense University Hospital	Odense	Denmark
6	Roskilde Hospital	Roskilde	Denmark
7	Aberdeen Royal Infirmary	Aberdeen	United Kingdom
8	Monklands Hospital	Airdrie	United Kingdom
9	Ysbyty Gwynedd Hospital	Bangor	United Kingdom
10	Royal United Hospital Bath	Bath	United Kingdom
11	Belfast City Hospital	Belfast	United Kingdom
12	Birmingham Heartland Hospital	Birmingham	United Kingdom
13	Queen Elizabeth Hospital	Birmingham	United Kingdom
14	Blackpool Victoria Hospital	Blackpool	United Kingdom
15	Ysbyty Glan Clwyd	Bodelwyddan	United Kingdom
16	Pilgrim Hospital	Boston	United Kingdom
17	Royal Bournemouth General Hospital	Bournemouth	United Kingdom
18	Bradford Royal Infirmary	Bradford	United Kingdom
19	Bristol Haematology & Oncology Centre	Bristol	United Kingdom
20	Addenbrooke's Hospital	Cambridge	United Kingdom
21	UHW	Cardiff	United Kingdom	CF14 4XN
22	University Hospital of Wales	Cardiff	United Kingdom
23	Cheltenham General Hospital	Cheltenham	United Kingdom
24	Countess of Chester Hospital	Chester	United Kingdom
25	St Richard's Hospital	Chichester	United Kingdom
26	University Hospital of Coventry and Warwickshire	Coventry	United Kingdom
27	Derby Teaching Hospital	Derby	United Kingdom
28	Russell Hall	Dudley	United Kingdom
29	Ninewells Hospital	Dundee	United Kingdom
30	Western General Hospital	Edinburgh	United Kingdom
31	Royal Devon & Exeter Hospital	Exeter	United Kingdom
32	Beatson West of Scotland Cancer Centre	Glasgow	United Kingdom
33	Hairmyres Hospital	Glasgow	United Kingdom
34	The New Victoria Hospital	Glasgow	United Kingdom
35	Gloucestershire Royal Hospital	Gloucester	United Kingdom
36	Royal Free Hospital	Hamstead	United Kingdom
37	Raigmore Hospital	Inverness	United Kingdom
38	Ipswich Hospital	Ipswich	United Kingdom
39	Crosshouse & Ayr Hospital	Irvine	United Kingdom
40	Kettering General Hospital	Kettering	United Kingdom
41	Victoria Hospital	Kirkcaldy	United Kingdom
42	Forth Valley Royal Hospital	Larbert	United Kingdom
43	St Jame's University Hospital	Leeds	United Kingdom
44	Leicester Royal Infirmary	Leicester	United Kingdom
45	Lincoln County Hospital	Lincoln	United Kingdom
46	Aintree University Hospital	Liverpool	United Kingdom
47	The Royal Liverpool University Hospital	Liverpool	United Kingdom
48	Guy's Hospital	London	United Kingdom
49	St Bartholomew's Hospital	London	United Kingdom
50	St George's Hospital	London	United Kingdom
51	The Royal Marsden	London	United Kingdom
52	University College London Hospital	London	United Kingdom
53	Maidstone District General Hospital	Maidstone	United Kingdom
54	Manchester Royal Infirmary	Manchester	United Kingdom
55	The Christie Hospital	Manchester	United Kingdom
56	The James Cook University Hospital	Middlesbrough	United Kingdom
57	Milton Keynes	Milton Keynes	United Kingdom
58	Freeman Hospital	Newcastle	United Kingdom
59	Northampton General Hospital	Northampton	United Kingdom
60	Norfolk & Norwich University	Norwich	United Kingdom
61	Nottingham University Hospital	Nottingham	United Kingdom
62	Royal Oldham Hospital	Oldham	United Kingdom
63	Churchill Hospital	Oxford	United Kingdom
64	Derriford Hospital	Plymouth	United Kingdom
65	Queen Alexandra Hospital	Portsmouth	United Kingdom
66	Whiston Hospital & St Helens	Prescot	United Kingdom
67	Queen's Hospital	Romford	United Kingdom
68	Salford Royal Hospital	Salford	United Kingdom
69	Salisbury District Hospital	Salisbury	United Kingdom
70	Wexham Park Hospital	Slough	United Kingdom
71	Southampton General Hospital	Southampton	United Kingdom
72	Stafford Hospital	Stafford	United Kingdom
73	University Hospital of Royal Stoke	Stoke-on-Trent	United Kingdom
74	Sunderland Royal Hospital	Sunderland	United Kingdom
75	St Helier Hospital	Sutton	United Kingdom
76	Singleton Hospital	Swansea	United Kingdom
77	Torbay District General Hospital	Torquay	United Kingdom
78	Royal Cornwall Hospital	Truro	United Kingdom
79	Hillingdon Hospital	Uxbridge	United Kingdom
80	Pinderfields Hospital	Wakefield	United Kingdom
81	Sandwell Hospital	West Bromwich	United Kingdom
82	Arrowe Park Hospital	Wirral	United Kingdom
83	Wishaw General Hospital	Wishaw	United Kingdom
84	New Cross Hospital	Wolverhampton	United Kingdom
85	Worcestershire Royal Hospital	Worcester	United Kingdom
86	Worthing Hospital	Worthing	United Kingdom
87	York Hospital	York	United Kingdom