Overview

The main purpose of this study is :

1. To establish which number of doses of gemtuzumab ozogamicin (up to a maximum of 3 doses) is tolerated and can be safety delivered in combination with cytarabine plus mitoxantrone or liposomal daunorubicin in induction
2. To compare mitoxantrone (anthracenedione) & cytarabine with liposomal daunorubicin (anthracycline) & cytarabine as induction therapy. (Randomisation 1 (R1) closed early to recruitment on 8th September 2017, due to liposomal daunorubicin manufacturing issues resulting in unavailability of the drug.)
3. To compare a single dose of gemtuzumab ozogamicin with the optimum tolerated number of doses of gemtuzumab ozogamicin (identified by the dose-finding study) when combined with induction chemotherapy.
4. To compare two consolidation regimens: high dose cytarabine (HD Ara-C) and fludarabine & cytarabine (FLA) in standard risk patients.
5. To compare the toxicity and effectiveness of two haemopoietic stem cell transplant (HSCT) conditioning regimens of different intensity: conventional myeloablative conditioning (MAC) with busulfan/cyclophosphamide and reduced intensity conditioning (RIC) with fludarabine/busulfan.

Eligibility

Inclusion Criteria:

Inclusion criteria for trial entry

• Diagnosis of acute myeloid leukaemia (AML) /high risk Myelodysplastic syndrome (MDS) (>10% blasts in the bone marrow)/isolated myeloid sarcoma (MS) (either de novo or secondary).
• Age <18 years at trial entry.
• No prior chemotherapy or biological therapy for AML/high risk MDS/isolated MS other than that permitted in the protocol.
• Normal cardiac function defined as fractional shortening ≥28% or ejection fraction ≥55%.
• Fit for protocol chemotherapy.
• Documented negative pregnancy test for female patients of childbearing potential.
• Patient agrees to use effective contraception (patients of child bearing potential).
• Written informed consent from the patient and/or parent/legal guardian.

Inclusion criteria for participation in the gemtuzumab ozogamicin dose finding study:

        Centres must be formally activated in order to be take part in the embedded dose escalation
        study. Please contact the trial office for further information.
          -  Patient meets the inclusion criteria for trial entry.
          -  Age:
               -  ≥12 months for the major dose finding study
               -  ≥ 12 weeks and <12 months for the minor dose finding study
          -  Normal renal function defined as calculated creatinine clearance ≥90ml/min/1.73m2.
          -  Normal hepatic function defined as total bilirubin ≤2.5 upper limit of normal (ULN)
             for age unless it is caused by leukaemic involvement or Gilbert's syndrome or similar
             disorder.
          -  Alanine transaminase (ALT) or aspartate transaminase (AST) ≤10 x ULN for age.
          -  Written informed consent from the patient and/or parent/legal guardian.
        Inclusion criteria for treatment with gemtuzumab ozogamicin for patients not participating
        in the gemtuzumab ozogamicin dose finding study or R2.
          -  Patient meets the inclusion criteria for trial entry (section 4.1.1)
          -  Age:
               -  ≥12 months
               -  ≥ 12 weeks
               -  ≥28 days and <12 weeks (patients will receive a maximum of one dose of gemtuzumab
                  ozogamicin)
          -  Normal renal function, defined as calculated creatinine clearance ≥90 ml/min/1.73m2
          -  Normal hepatic function, defined as total bilirubin ≤2.5 upper limit of normal (ULN)
             for age and not due to leukaemic involvement or Gilbert's syndrome or similar disorder
          -  ALT or AST ≤10 x ULN for age
          -  Written informed consent from the patient and/or parent/legal guardian
        Inclusion criteria for participation in R2.(once open to randomisation in the applicable
        age group)
        • Patient meets the inclusion criteria for trial entry
        Patient age:
          -  ≥12 months
          -  ≥12 weeks (once R2 open in patients aged ≥12 weeks and <12 months)
          -  Normal renal function defined as calculated creatinine clearance ≥90ml/min/1.73m2.
          -  Normal hepatic function defined as total bilirubin ≤2.5 ULN for age and not due to
             leukaemic involvement or Gilbert's syndrome or similar disorder.
          -  ALT or AST ≤10 x ULN for age.
          -  Written informed consent from the patient and/or parent/legal guardian.
        Inclusion criteria for participation in R3.
          -  Patient meets the inclusion criteria for trial entry
          -  Induction treatment as per MyeChild 01 protocol or treated with 2 courses of
             mitoxantrone & cytarabine off trial.
          -  Minimal residual disease (MRD) response (performed in MyeChild 01 centralised
             laboratories, see national MyeChild 01 Laboratory Manual):
               -  Patients with good risk cytogenetics/molecular genetics and a MRD level <0.1% by
                  flow after course 2, or a decrease in transcript levels of >3 logs after course 2
                  for those with an informative molecular marker, but without an informative marker
                  of sufficient sensitivity for flow MRD monitoring or
               -  Patients with intermediate risk cytogenetics/molecular genetics with a MRD level
                  <0.1% by flow after course 1 and course 2, or a decrease in transcript levels of
                  >3 logs after course 1 and course 2 for those with an informative molecular
                  marker, but without an informative marker of sufficient sensitivity for flow MRD
                  monitoring.
          -  Written informed consent from the patient and/or parent/legal guardian.
        Inclusion criteria for participation in R4.
          -  Patient meets the inclusion criteria for trial entry
          -  Induction treatment as per MyeChild 01 protocol or treated with 1 or 2 courses of
             mitoxantrone & cytarabine ± treatment intensification with fludarabine, cytarabine &
             idarubicin (FLA-Ida) off trial.
          -  Patient is in complete remission (CR) or CR with incomplete blood count recovery (CRi)
             defined as <5% blasts confirmed by flow cytometry/ molecular/FISH in a bone marrow
             aspirate taken within 6 weeks prior to randomisation to R4.
          -  Patient meets one of the following criteria and is a candidate for HSCT as per the
             protocol:
               -  High risk after course 1 (all patients with poor risk cytogenetics and patients
                  with intermediate risk cytogenetics who fail to achieve CR/CRi).
               -  Intermediate risk cytogenetics with MRD >0.1% after course 1 and 2 measured by
                  flow. If no flow MRD marker of sufficient sensitivity is identified, a molecular
                  MRD marker with a sensitivity of >0.1% may be used.
               -  Good risk cytogenetics with flow MRD >0.1% confirmed by a decrease in molecular
                  MRD of <3 logs or rising transcript levels after course 3 despite treatment
                  intensification (FLA-Ida) and after discussion with the Clinical Co-ordinators.
          -  Availability of a 9-10/10 human leukocyte antigen (HLA) matched family or unrelated
             donor or 5-8/8 matched cord blood unit with an adequate cell dose as defined by the
             protocol section 17.1.
          -  Written informed consent from the patient and/or parent/legal guardian.
        Exclusion Criteria:
        Exclusion criteria for all randomisations
          -  Acute Promyelocytic Leukaemia.
          -  Myeloid Leukaemia of Down Syndrome.
          -  Blast crisis of chronic myeloid leukaemia.
          -  Relapsed or refractory AML.
          -  Bone marrow failure syndromes.
          -  Prior anthracycline exposure which would inhibit the delivery of study anthracyclines.
          -  Concurrent treatment or administration of any other experimental drug or with any
             other biological therapy for AML/high risk MDS/isolated MS.
          -  Pregnant or lactating females.