NCT02724163 · CITED IN SOURCE DOCUMENTS

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

An NCI or FDA source cites this study. A citation does not establish that it applies to an individual diagnosis.

Phase: PHASE3
Status at capture: ACTIVE NOT RECRUITING
Registry last update: 2026-06-29

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.

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What did the study report?

Outcomes, safety and baseline populations are separate source sections. Quality-of-life measures appear under their original outcome titles.

No posted result sections were captured. Registered plans do not establish that a treatment works.

Who could take part

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.
healthy Volunteers: false
maximum Age: 17 Years
sex: ALL
std Ages: CHILD

Treatment arms and interventions

arm Groups

description
Course 1 * Mitoxantrone: 12 mg/m2 daily by IV infusion over 1 hour on days 1, 2, 3 and 4 (total 4 doses). * Cytarabine:100 mg/m2 12 hourly by IV bolus on days 1-10 inclusive (total 20 doses). Course 2 * Mitoxantrone: 12 mg/m2 daily by IV infusion over 1 hour on days 1, 2 and 3 (total 3 doses). * Cytarabine: 100 mg/m2 12 hourly by IV bolus on days 1-8 inclusive (total 16 doses).
intervention Names
Drug: Mitoxantrone
Drug: Cytarabine
label
Mitoxantrone
type
ACTIVE_COMPARATOR
description
Randomisation 1 (R1)) closed early to recruitment on 8th September 2017, due to liposomal daunorubicin manufacturing issues resulting in unavailability of the drug. Course 1 * Liposomal daunorubicin: 80 mg/m2 daily by 1 hour IV infusion on days 1, 3 and 5 (total 3 doses). * Cytarabine: 100 mg/m2 12 hourly by IV bolus on days 1-10 inclusive (total 20 doses). Course 2 * Liposomal daunorubicin: 60 mg/m2 daily by 1 hour IV infusion on days 1, 3 and 5 (total 3 doses). * Cytarabine: 100 mg/m2 12 hourly by IV bolus on days 1-8 inclusive (total 16 doses).
intervention Names
Drug: Liposomal daunorubicin
Drug: Cytarabine
label
Liposomal daunorubicin
type
EXPERIMENTAL
description
* Cohort 1: 1x3mg/m2 IV infusion over 2hours on day 4. * Cohort 2: 2x3mg/m2 IV infusion over 2hours on day 4 and day 7. * Cohort 3: 3x3mg/m2 IV infusion over 2hours on days 4, 7 and 10.
intervention Names
Drug: Gemtuzumab ozogamicin
label
Gemtuzumab Ozogamicin Dose Finding Study
type
EXPERIMENTAL
description
Two courses of Cytarabine: 3 g/m2 12 hourly by IV infusion over 4 hours on days 1, 3 and 5 (total 6 doses).
intervention Names
Drug: Cytarabine
label
High dose cytarabine
type
ACTIVE_COMPARATOR
description
Two courses of: * Fludarabine: 30 mg/m2 daily by IV infusion over 30 minutes on days 1-5 inclusive (total 5 doses). * Cytarabine: 2 g/m2 daily by IV infusion over 4 hours on days 1-5 inclusive (total 5 doses).The cytarabine infusion should be started 4 hours after the start of the fludarabine infusion
intervention Names
Drug: Fludarabine
Drug: Cytarabine
label
Fludarabine & cytarabine
type
EXPERIMENTAL
description
* Busulfan Area Under the Curve (AUC) 70-100mg/L x hr by IV infusion over 3 hours, given 12 hourly on days -10 to -7 (8 doses). * Cyclophosphamide 50mg/kg/day by IV infusion over 1 hour, on days -5 to -2 (4 doses).
intervention Names
Drug: Busulfan
Drug: Cyclophosphamide
label
Myeloablative conditioning
type
ACTIVE_COMPARATOR
description
* Busulfan AUC60-65mg/L X hr by IV infusion over 3 hours, given 12 hourly on days -5 to -2 (8 doses). * Fludarabine 30mg/m2/day by IV infusion over 30 minutes on days -8 to -3 (6 doses).
intervention Names
Drug: Fludarabine
Drug: Busulfan
label
Reduced intensity conditioning
type
EXPERIMENTAL

interventions

arm Group Labels
Gemtuzumab Ozogamicin Dose Finding Study
description
Antibody-conjugated chemotherapy agent.
name
Gemtuzumab ozogamicin
other Names
Mylotarg
type
DRUG
arm Group Labels
Liposomal daunorubicin
description
Anthracycline (Randomisation 1 (R1)) closed early to recruitment on 8th September 2017, due to liposomal daunorubicin manufacturing issues resulting in unavailability of the drug.
name
Liposomal daunorubicin
type
DRUG
arm Group Labels
Mitoxantrone
description
DNA-reactive agent
name
Mitoxantrone
type
DRUG
arm Group Labels
Fludarabine & cytarabine
Reduced intensity conditioning
description
A water-soluble fluorinated nucleotide analogue of the antiviral agent vidarabine.
name
Fludarabine
type
DRUG
arm Group Labels
Fludarabine & cytarabine
High dose cytarabine
Liposomal daunorubicin
Mitoxantrone
description
Pyrimidine nucleoside analogue, an antineoplastic agent.
name
Cytarabine
type
DRUG
arm Group Labels
Myeloablative conditioning
Reduced intensity conditioning
description
Alkylsulfonate
name
Busulfan
type
DRUG
arm Group Labels
Myeloablative conditioning
description
A nitrogen mustard alkylating agent from the oxazaphosphorine group
name
Cyclophosphamide
type
DRUG

Study design

allocation

RANDOMIZED

intervention Model

PARALLEL

masking Info

masking: NONE

primary Purpose

TREATMENT

Enrollment

count: 700
type: ESTIMATED

Registered outcome plans (not posted results)

primary Outcomes

measure
Incidence of dose limiting toxicities (DLTs).
time Frame
Incidence of DLTs will be evaluated up to day 45 post course 1 and course 2 of induction chemotherapy.
description
The primary analysis will be carried out once the last patient has a minimum of 1 year follow up. EFS estimates will be presented at 24 months along with 95% confidence intervals.
measure
Event Free Survival (EFS).
time Frame
Event free survival (EFS) will be evaluated as the time from randomisation one to the first event, up to 16 years.
description
The primary analysis will be carried out once the last patient has a minimum of 1 year follow up. EFS estimates will be presented at 24 months along with 95% confidence intervals.
measure
Event Free Survival (EFS).
time Frame
Event free survival (EFS) will be evaluated as the time from randomisation two to the first event, up to 16 years..
description
The primary analysis will be carried out once the last patient has a minimum of 1 year follow up. RFS estimates will be presented at 24 months along with 95% confidence intervals.
measure
Relapse free survival (RFS).
time Frame
Relapse free survival (RFS) will be evaluated as the time of randomisation three to the first relapse or death from any cause, up to 16 years.
description
Early treatment related adverse reactions defined as the incidence by day 100 post-transplant of grade 3-5 toxicity for the following systems using the National Cancer Institute (NCI) Common Terminology Criteria v4: * Cardiac (pericardial effusion/Left ventricular systolic dysfunction). * Respiratory, thoracic and mediastinal (hypoxia/pneumonitis). * Gastrointestinal (GI) (diarrhoea/typhlitis/upper and lower GI haemorrhage). * Investigations (bilirubin). * Renal and Urinary (acute kidney injury/haematuria). * Nervous system (seizure).
measure
Early treatment related adverse reactions.
time Frame
Early treatment related adverse reactions will be evaluated at day 100 post-transplant.
description
The primary analysis will be carried out once the last patient has a minimum of 1 year follow up. RFS estimates will be presented at 12 months along with 95% confidence intervals.
measure
Relapse free survival (RFS).
time Frame
Relapse free survival (RFS) will be evaluated as the time of randomisation four to the first relapse or death from any cause, up to 16 years.

secondary Outcomes

measure
The nature, incidence and severity of adverse events (AEs) (gemtuzumab ozogamicin dose finding study).
time Frame
Evaluated by day 45 post course 1 and course 2.
description
Response is assessed by morphology confirmed by MRD levels measured by flow cytometry, molecular methods or fluorescence in situ hybridisation (FISH) as defined in the protocol, in combination with platelet and neutrophil counts. These results of these assessments will be combined to determine the patient's disease response using the response criteria defined in the protocol.
measure
Response measured by bone marrow assessment using morphology and minimal residual disease (MRD) assessment (gemtuzumab ozogamicin dose finding study).
time Frame
Evaluated by day 45 post course 1 and course 2.
description
Serum PK parameters will be measured using serial samples taken at multiple timepoints during course 1 and at 1 month post first dose of gemtuzumab ozogamicin as defined in the protocol by dose cohort.
measure
Serum pharmacokinetic (PK) parameters of gemtuzumab ozogamicin: Clearance (CL) (gemtuzumab ozogamicin dose finding study)
time Frame
Evaluated up to one month after the first dose of gemtuzumab ozogamicin.
description
Serum PK parameters will be measured using serial samples taken at multiple timepoints during course 1 and at 1 month post first dose of gemtuzumab ozogamicin as defined in the protocol by dose cohort.
measure
Serum pharmacokinetic (PK) parameters of gemtuzumab ozogamicin: Volume of distribution (Vd) (gemtuzumab ozogamicin dose finding study)
time Frame
Evaluated up to one month after the first dose of gemtuzumab ozogamicin.
description
Evaluated using remission status at completion of course 1 and course 2.
measure
Complete remission (CR) (R1 & R2).
time Frame
Evaluated and presented at the completion of course 1 and 2 of treatment up to a maximum of 45 days post each course of treatment
description
Evaluated as resistant disease, induction death or not evaluable.This will be evaluated at completion of course 1 and 2 of treatment, once patient's blood counts have recovered or reason for non-recovery has been determined.
measure
Reasons for failure to achieve CR (R1 & R2).
time Frame
Evaluated and presented at the completion of course 1 and 2 of treatment, up to a maximum of 45 days post each course of treatment.
description
The primary analysis will be carried out once the last patient has a minimum of 1 year follow up. CIR estimates will be presented at 24 months along with 95% confidence intervals for randomisations 1, 2 and 3, and at 12 months for randomisation 4.
measure
Cumulative Incidence of Relapse (CIR) (all randomisations).
time Frame
Evaluated as time from randomisation to the relevant question to relapse, up to 16 years.
description
The primary analysis will be carried out once the last patient has a minimum of 1 year follow up. DCR estimates will be presented at 24 months along with 95% confidence intervals.
measure
Death in CR (DCR) (R1, R2 & R3).
time Frame
Evaluated as time from randomisation to relevant question to date of death from any cause in patients who have achieved CR, up to 16 years.
description
The primary analysis will be carried out once the last patient has a minimum of 1 year follow up. EFS estimates will be presented at 24 months along with 95% confidence intervals.
measure
Event Free Survival (EFS) (R1, R2 & R3).
time Frame
Evaluated as time from randomisation to the relevant question to the first of failure to achieve CR (recorded as an event on day 1), relapse, secondary malignancy or death from any cause, up to 16 years.
description
The primary analysis will be carried out once the last patient has a minimum of 1 year follow up. OS estimates will be presented at 24 months along with 95% confidence intervals for randomisations 1, 2 and 3, and at 12 months for randomisation 4.
measure
Overall Survival (OS) (all randomisations).
time Frame
Evaluated as time from randomisation to the relevant question to death from any cause or date last seen for patients who are alive at the end of the trial, up to 16 years.
measure
Incidence of toxicities (all randomisations).
time Frame
Evaluated 30 days after end of trial treatment.
measure
Incidence of cardiotoxicity (R1, R2 & R4 only).
time Frame
Evaluated 30 days after end of trial treatment.

Full study description

brief Summary: 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.
detailed Description: 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.

Source references

Source notices and limitations

Discovery and provenance

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ref="#cit/section_6.24">24</a>] Because this is the recommended dosing method for adults, this schedule is now being evaluated in the <a href="/clinicaltrials/NCT02724163">MyeChild 01 (NCT02724163)</a> phase III study for pediatric patients with de novo AML in the United Kingdom.</p><p id="_2165" tabindex="-1">The characteristic
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</a>] Because this is the recommended dosing method for adults, this schedule is now being evaluated in the <a href="/clinicaltrials/NCT02724163">MyeChild 01 (NCT02724163)</a> phase III study for pediatric patients with de novo AML in the United Kingdom.</p><p id="_2165" tabindex="-1">The characteristics of CD33, the target of g
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to be safe and effective in adults with de novo AML;[<a href="#cit/section_7.29">29</a>] it is now being evaluated in the MyeChild01 (<a href="/clinicaltrials/NCT02724163">NCT02724163</a>) phase III study for pediatric patients with de novo AML in the United Kingdom.</li></ul></div> </li></ol></div> </section> <
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d effective in adults with de novo AML;[<a href="#cit/section_7.29">29</a>] it is now being evaluated in the MyeChild01 (<a href="/clinicaltrials/NCT02724163">NCT02724163</a>) phase III study for pediatric patients with de novo AML in the United Kingdom.</li></ul></div> </li></ol></div> </section> <section id="_
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Childhood Acute Myeloid Leukemia Treatment (PDQ®)–Health Professional Version
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Preserved source evidence · Not medical advice