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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

Patients with known adverse karyotype

5 cycles of Vosaroxin and Decitabine therapy

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

Prior to Course 2 - Patients that received DA plus GO in course 1 and MRD negative PC1

Randomisation to receive AC220 or not

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)

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)

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 A Mylotarg plus DA Versus CPX-351

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 B 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.

Arm D Small molecule or Not

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 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 fashion between CPX given on days 1, 3 and 5 (3 doses) and CPX given on days 1 and 3 (2 doses).

Arm E CPX-351 (200 V 300)

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.

Arm F DA V IDAC

Sophie King

Marianne Severinsen, MD

Hans B Ommen, MD

Claudia Schöllkopf, MD

Ulrik M Overgaard, MD

Duruta Weber, MD

Peter Møller

Dominic Culligan, MD

John Murphy, MD

Jim Seale, MD

Chris Knechtli, MD

Mary McMullin, MD

Manos Nikolousis, MD

Charles Craddock, DPhil

Paul Cahalin, MD

Earnest Heartin, MD

Charlotte Kallmeyer, MD

Joseph Chacko, MD

Sam Ackroyd, MD

Priyanka Mehta, MD

Kiran Tawana, MD

Steve Knapper

Steve Knapper, MD

Adam Rye, MD

Arvind Pillai, MD

Santosh Narat, MD

Beth Harris, MD

Ian Amott, MD

Rupert Hipkins, MD

Sudhir Tauro, MD

Peter Johnson, MD

Jason Coppell, MD

Mhairi Copland, MD

Gail Loud, MD

Panagiotis Kottaridis, MD

Caroline Duncan, MD

Mahesh Prahladan, MD

William Gordon, MD

Mark Kwan, MD

Victoria Campbell, MD

Hugh Edwards, MD

Richard Kelly, MD

Katherine Hodgson, MD

Vikram Singh, MD

Amit Patel, MD

Kavita Raj, MD

Mathew Smith, MD

Matthias Klammer, MD

David Taussig, M.D

A Khwaja, MD

Evangelia Dimitriadou, MD

Eleni Tholouli, MD

Mike Dennis, MD

Ray Dang, MD

Moez Dungarwalla, MD

Gail Jones, MD

Jane Parker, MD

Angela Collins, MD

Nigel Russell, MD

David Osborne, MD

Paresh Vyas, MD

Patrick Medd, MD

Robert Corser, MD

Toby Nicholson, MD

Paul Greaves, MD

Rowena Thomas-Dewing, MD

Jonathan Cullis, MD

Mark Offer, MD

Deborah Richardon, MD

Paul Revell, MD

Srivinas Pillai, MD

Shikha Chattree, MD

Simon Stern, MD

Unmesh Monite, MD

Deborah Turner, MD

Bryson Pottinger, MD

Richard Kaczmarski, MD

Paul Moreton, MD

Farooq Wandroo, MD

Ranjit Dasgupta, MD

Richard Whitmill, MD

Nicholas Pemberton, MD

Lee Bond, MD

Nigel Russell, Prof

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.

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

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

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

Cancer Research UK

Cardiff University

Prof

Spots Global Cancer Trial Database for arm f da v idac