International Randomised Phase III Clinical Trial in Children With Acute Myeloid Leukaemia
NCT ID: NCT02724163
Last Updated: 2021-10-08
Study Results
The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.
Basic Information
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RECRUITING
PHASE3
700 participants
INTERVENTIONAL
2016-04-30
2032-12-31
Brief Summary
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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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Detailed Description
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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.
Conditions
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Study Design
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RANDOMIZED
PARALLEL
TREATMENT
NONE
Study Groups
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Mitoxantrone
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).
Mitoxantrone
DNA-reactive agent
Cytarabine
Pyrimidine nucleoside analogue, an antineoplastic agent.
Liposomal daunorubicin
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).
Liposomal daunorubicin
Anthracycline
(Randomisation 1 (R1)) closed early to recruitment on 8th September 2017, due to liposomal daunorubicin manufacturing issues resulting in unavailability of the drug.
Cytarabine
Pyrimidine nucleoside analogue, an antineoplastic agent.
Gemtuzumab Ozogamicin Dose Finding Study
* 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.
Gemtuzumab ozogamicin
Antibody-conjugated chemotherapy agent.
High dose cytarabine
Two courses of Cytarabine: 3 g/m2 12 hourly by IV infusion over 4 hours on days 1, 3 and 5 (total 6 doses).
Cytarabine
Pyrimidine nucleoside analogue, an antineoplastic agent.
Fludarabine & cytarabine
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
Fludarabine
A water-soluble fluorinated nucleotide analogue of the antiviral agent vidarabine.
Cytarabine
Pyrimidine nucleoside analogue, an antineoplastic agent.
Myeloablative conditioning
* 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).
Busulfan
Alkylsulfonate
Cyclophosphamide
A nitrogen mustard alkylating agent from the oxazaphosphorine group
Reduced intensity conditioning
* 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).
Fludarabine
A water-soluble fluorinated nucleotide analogue of the antiviral agent vidarabine.
Busulfan
Alkylsulfonate
Interventions
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Gemtuzumab ozogamicin
Antibody-conjugated chemotherapy agent.
Liposomal daunorubicin
Anthracycline
(Randomisation 1 (R1)) closed early to recruitment on 8th September 2017, due to liposomal daunorubicin manufacturing issues resulting in unavailability of the drug.
Mitoxantrone
DNA-reactive agent
Fludarabine
A water-soluble fluorinated nucleotide analogue of the antiviral agent vidarabine.
Cytarabine
Pyrimidine nucleoside analogue, an antineoplastic agent.
Busulfan
Alkylsulfonate
Cyclophosphamide
A nitrogen mustard alkylating agent from the oxazaphosphorine group
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
* 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.
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.
* 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.
* 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
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.
* 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.
* 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
* 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.
17 Years
ALL
No
Sponsors
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Assistance Publique - Hôpitaux de Paris
OTHER
Cancer Research UK
OTHER
National Cancer Institute, France
OTHER_GOV
Pfizer
INDUSTRY
University of Birmingham
OTHER
Responsible Party
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Principal Investigators
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Brenda Gibson
Role: PRINCIPAL_INVESTIGATOR
Royal Hospital for Children Glasgow
Locations
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Women and Children's Hospital Adelaide
Adelaide, , Australia
Queensland Children's Hospital
Brisbane, , Australia
Monash Children's Hospital
Melbourne, , Australia
Royal Childrens Hospital
Melbourne, , Australia
John Hunter Children's Hopsital
New Lambton Heights, , Australia
Perth Children's Hospital
Perth, , Australia
Sydney Children's Hospital
Sydney, , Australia
The Childrens Hospital At Westmead
Westmead, , Australia
Centre Hospitalier Universitaire Amiens - Picardie
Amiens, , France
Centre Hospitalier Universitaire D'angers
Angers, , France
Centre Hospitalier Regional Universitaire Besancon - Hopital Jean Minjoz
Besançon, , France
Centre Hospitalier Universitaire De Bordeaux - Hopital Pellegrin
Bordeaux, , France
Centre Hospitalier Regional Universitaire Brest - Hopital Morvan
Brest, , France
Centre Hospitalier Universitaire De Caen
Caen, , France
Centre Hospitalier Universitaire De Clermont-ferrand
Clermont-Ferrand, , France
Centre Hospitalier Universitaire Dijon Bourgogne - Hopital D'enfants
Dijon, , France
Centre Hospitalier Universitaire De Grenoble
Grenoble, , France
Hopital Jeanne Dr Flandre
Lille, , France
Centre Hospitalier Universitaire De Limoges
Limoges, , France
Centre Leon Berard
Lyon, , France
Hopital De La Timone
Marseille, , France
Centre Hospitalier Regional Universitaire Montpellier - Hopital Arnaud-de-villeneuve
Montpellier, , France
Centre Hospitalier Universitaire De Nancy
Nancy, , France
Centre Hospitalier Universitaire De Nantes
Nantes, , France
Centre Hospitalier Universitaire De NICE
Nice, , France
Hopital Armand Trousseau
Paris, , France
Hopital Robert Debre
Paris, , France
Hopital Saint Louis
Paris, , France
Centre Hospitalier Universitaire De Poitiers
Poitiers, , France
Chu De Reims
Reims, , France
Centre Hospitalier Universitaire De Rennes - Hopital Sud
Rennes, , France
Centre Hospitalier Universitaire De Rouen
Rouen, , France
Centre Hospitalier Universitaire Saint-etienne
Saint-Etienne, , France
Strasbourg Hautepierre
Strasbourg, , France
Centre Hospitalier Universitaire De Toulouse - Hopital Des Enfants
Toulouse, , France
Centre Hospitalier Regional Universitaire De Tours - Hopital Clocheville
Tours, , France
Our Lady's Hospital for Sick Children
Dublin, , Ireland
Starship Childrens Hospital
Auckland, , New Zealand
Christchurch Hospital
Christchurch, , New Zealand
Kantonsspital Aarau
Aarau, , Switzerland
Universitäts-Kinderspital beider
Basel, , Switzerland
Ospedale San Giovanni
Bellinzona, , Switzerland
Inselspital Bern
Bern, , Switzerland
Hug Hopitaux Universitaires De Geneve
Geneva, , Switzerland
Centre Hospitalier Universitaire Vaudois Chuv Lausanne
Lausanne, , Switzerland
Luzerner Kantonspital - Kinderspital Luzern
Lucerne, , Switzerland
Ostschweizer Kinderspital
Sankt Gallen, , Switzerland
University Children's Hospital Zurich
Zurich, , Switzerland
Royal Belfast Hospital for Sick Children
Belfast, County Antrim, United Kingdom
Royal Aberdeen Children's Hospital
Aberdeen, , United Kingdom
Aberdeen Royal Infirmary, NHS Grampian
Aberdeen, , United Kingdom
Birmingham Children's Hospital NHS Foundation Trust
Birmingham, , United Kingdom
University Hospitals Bristol NHS Foundation Trust
Bristol, , United Kingdom
Addenbrookes Hospital, Cambridge University Hospitals NHS Foundation Trust
Cambridge, , United Kingdom
Cardiff and Vale University Health Board, Noah's Ark Children's Hospital for Wales
Cardiff, , United Kingdom
NHS Lothian, Royal Hospital for Sick Children
Edinburgh, , United Kingdom
NHS Greater Glasgow and Clyde, The Royal Hospital for Children
Glasgow, , United Kingdom
Leeds General Infirmary, Leeds Teaching Hospitals NHS Trust
Leeds, , United Kingdom
Alder Hey Children's NHS Foundation Trust
Liverpool, , United Kingdom
University College London Hospitals NHS Foundation Trust
London, , United Kingdom
The Royal Marsden NHS Foundation Trust
London, , United Kingdom
Great Ormond Street Hospital For Children NHS Trust
London, , United Kingdom
Royal Manchester Childrens' Hospital , Central Manchester University Hospitals NHS Foundation Trust
Manchester, , United Kingdom
The Newcastle Upon Tyne Hospitals NHS Foundation Trust
Newcastle, , United Kingdom
Nottingham University Hospitals NHS Trust
Nottingham, , United Kingdom
John Radcliffe Hospital, Oxford Radcliffe Hospitals NHS Trust
Oxford, , United Kingdom
Sheffield Children's NHS Foundation Trust
Sheffield, , United Kingdom
Southampton University Hospitals NHS Trust
Southampton, , United Kingdom
Countries
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Central Contacts
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Facility Contacts
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Carley Purcell
Role: primary
Carley Purcell
Role: primary
Carley Purcell
Role: primary
Carley Purcell
Role: primary
Carley Purcell
Role: primary
Carley Purcell
Role: primary
Carley Purcell
Role: primary
Carley Purcell
Role: primary
Corinna Phillips
Role: primary
Other Identifiers
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2014-005066-30
Identifier Type: EUDRACT_NUMBER
Identifier Source: secondary_id
RG_14-088
Identifier Type: -
Identifier Source: org_study_id
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