International Randomised Phase III Clinical Trial in Children With Acute Myeloid Leukaemia (Myechild01)
Acute Myeloid Leukaemia
About this trial
This is an interventional treatment trial for Acute Myeloid Leukaemia focused on measuring Acute Myeloid Leukaemia, Children, Gemtuzumab ozogamicin, Liposomal daunorubicin, Mitoxantrone, Randomised controlled trial, Risk stratification, Minimal residual disease, Stem cell transplant
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.
Sites / Locations
- Women and Children's Hospital AdelaideRecruiting
- Queensland Children's HospitalRecruiting
- Monash Children's HospitalRecruiting
- Royal Childrens HospitalRecruiting
- John Hunter Children's HopsitalRecruiting
- Perth Children's HospitalRecruiting
- Sydney Children's HospitalRecruiting
- The Childrens Hospital At WestmeadRecruiting
- Centre Hospitalier Universitaire Amiens - PicardieRecruiting
- Centre Hospitalier Universitaire D'angersRecruiting
- Centre Hospitalier Regional Universitaire Besancon - Hopital Jean MinjozRecruiting
- Centre Hospitalier Universitaire De Bordeaux - Hopital PellegrinRecruiting
- Centre Hospitalier Regional Universitaire Brest - Hopital MorvanRecruiting
- Centre Hospitalier Universitaire De CaenRecruiting
- Centre Hospitalier Universitaire De Clermont-ferrandRecruiting
- Centre Hospitalier Universitaire Dijon Bourgogne - Hopital D'enfantsRecruiting
- Centre Hospitalier Universitaire De GrenobleRecruiting
- Hopital Jeanne Dr FlandreRecruiting
- Centre Hospitalier Universitaire De LimogesRecruiting
- Centre Leon BerardRecruiting
- Hopital De La TimoneRecruiting
- Centre Hospitalier Regional Universitaire Montpellier - Hopital Arnaud-de-villeneuveRecruiting
- Centre Hospitalier Universitaire De NancyRecruiting
- Centre Hospitalier Universitaire De NantesRecruiting
- Centre Hospitalier Universitaire De NICERecruiting
- Hopital Armand TrousseauRecruiting
- Hopital Robert DebreRecruiting
- Hopital Saint LouisRecruiting
- Centre Hospitalier Universitaire De PoitiersRecruiting
- Chu De ReimsRecruiting
- Centre Hospitalier Universitaire De Rennes - Hopital SudRecruiting
- Centre Hospitalier Universitaire De RouenRecruiting
- Centre Hospitalier Universitaire Saint-etienneRecruiting
- Strasbourg HautepierreRecruiting
- Centre Hospitalier Universitaire De Toulouse - Hopital Des EnfantsRecruiting
- Centre Hospitalier Regional Universitaire De Tours - Hopital ClochevilleRecruiting
- Our Lady's Hospital for Sick ChildrenRecruiting
- Starship Childrens HospitalRecruiting
- Christchurch HospitalRecruiting
- Kantonsspital AarauRecruiting
- Universitäts-Kinderspital beiderRecruiting
- Ospedale San GiovanniRecruiting
- Inselspital BernRecruiting
- Hug Hopitaux Universitaires De GeneveRecruiting
- Centre Hospitalier Universitaire Vaudois Chuv LausanneRecruiting
- Luzerner Kantonspital - Kinderspital LuzernRecruiting
- Ostschweizer KinderspitalRecruiting
- University Children's Hospital ZurichRecruiting
- Royal Belfast Hospital for Sick ChildrenRecruiting
- Royal Aberdeen Children's HospitalRecruiting
- Aberdeen Royal Infirmary, NHS GrampianRecruiting
- Birmingham Children's Hospital NHS Foundation TrustRecruiting
- University Hospitals Bristol NHS Foundation TrustRecruiting
- Addenbrookes Hospital, Cambridge University Hospitals NHS Foundation TrustRecruiting
- Cardiff and Vale University Health Board, Noah's Ark Children's Hospital for WalesRecruiting
- NHS Lothian, Royal Hospital for Sick ChildrenRecruiting
- NHS Greater Glasgow and Clyde, The Royal Hospital for ChildrenRecruiting
- Leeds General Infirmary, Leeds Teaching Hospitals NHS TrustRecruiting
- Alder Hey Children's NHS Foundation TrustRecruiting
- University College London Hospitals NHS Foundation TrustRecruiting
- The Royal Marsden NHS Foundation TrustRecruiting
- Great Ormond Street Hospital For Children NHS TrustRecruiting
- Royal Manchester Childrens' Hospital , Central Manchester University Hospitals NHS Foundation TrustRecruiting
- The Newcastle Upon Tyne Hospitals NHS Foundation TrustRecruiting
- Nottingham University Hospitals NHS TrustRecruiting
- John Radcliffe Hospital, Oxford Radcliffe Hospitals NHS TrustRecruiting
- Sheffield Children's NHS Foundation TrustRecruiting
- Southampton University Hospitals NHS TrustRecruiting
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm 4
Arm 5
Arm 6
Arm 7
Active Comparator
Experimental
Experimental
Active Comparator
Experimental
Active Comparator
Experimental
Mitoxantrone
Liposomal daunorubicin
Gemtuzumab Ozogamicin Dose Finding Study
High dose cytarabine
Fludarabine & cytarabine
Myeloablative conditioning
Reduced intensity conditioning
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).
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).
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.
Two courses of Cytarabine: 3 g/m2 12 hourly by IV infusion over 4 hours on days 1, 3 and 5 (total 6 doses).
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
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 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).