International Randomised Phase III Clinical Trial in Children With Acute Myeloid Leukaemia

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.

MyeChild 01 is an international phase III clinical trial in children with acute myeloid leukaemia (AML); a disease with significant mortality. It will compare two induction chemotherapy regimens: mitoxantrone and cytarabine (current standard treatment) with liposomal daunorubicin and cytarabine. This will test liposomal daunorubicin, which is believed to be less cardiotoxic than similar conventional drugs, although this is unproven. (Randomisation 1 (R1) closed early to recruitment on 8th September 2017, due to liposomal daunorubicin manufacturing issues resulting in unavailability of the drug.)

Patients responding well to induction chemotherapy are eligible for a randomisation of two consolidation regimens: high dose cytarabine (current standard treatment) or fludarabine and cytarabine (FLA); a regimen commonly used in patients with relapsed disease, testing whether FLA is more effective in front line therapy than standard consolidation treatment. Patients with cytogenetic features associated with a higher risk of relapse and those responding sub-optimally to induction treatment are candidates for haemopoietic stem cell transplant (HSCT) and are eligible for a randomisation comparing two HSCT conditioning regimens: myeloablative conditioning (MAC) (current UNited Kingdom (UK) standard) or reduced intensity conditioning (RIC). HSCT has not consistently shown benefit in high risk patients because the mortality associated with the procedure has outweighed the advantage from a reduction in relapse risk. This will test whether reducing the intensity of conditioning improves survival by reducing transplant related deaths without increasing the relapse rate. The trial incorporates a dose finding study for gemtuzumab ozogamicin. The aim is to identify the optimum tolerated number of doses of gemtuzumab ozogamicin (up to a total of 3 doses), which can be safely combined with either of the induction chemotherapy regimens and then to compare this number of doses with one dose of gemtuzumab ozogamicin. The intensity of treatment will be directed by cytogenetics/molecular genetics and response assessed by minimal residual disease (MRD) levels measured by flow cytometry and molecular methodology.

Eligibility Criteria:
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.