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

Acute Myeloid Leukaemia Clinical Trial

— Myechild01  

Official title:

International Randomised Phase III Clinical Trial in Children With Acute Myeloid Leukaemia - Incorporating an Embedded Dose Finding Study for Gemtuzumab Ozogamicin in Combination With Induction Chemotherapy

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT02724163
• Other study ID #: RG_14-088
• Secondary ID: 2014-005066-30
• Status: Recruiting
• Phase: Phase 3
• Start date: April 2016
• Est. completion date: December 2032

Study information

• Verified date: September 2021
• Source: University of Birmingham
• Contact: Christina Ryan
• Phone: 01214151049
• Email: myechild01[@]trials.bham.ac.uk
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 700
• Est. completion date: December 2032
• Est. primary completion date: December 2031
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A to 17 Years

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.

Related Conditions & MeSH terms

• Acute Myeloid Leukaemia
• Leukemia
• Leukemia, Myeloid
• Leukemia, Myeloid, Acute

Intervention

Drug:
• 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

Locations

Country	Name	City	State
Australia	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
France	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-Étienne
France	Strasbourg Hautepierre	Strasbourg
France	Centre Hospitalier Universitaire De Toulouse - Hopital Des Enfants	Toulouse
France	Centre Hospitalier Regional Universitaire De Tours - Hopital Clocheville	Tours
Ireland	Our Lady's Hospital for Sick Children	Dublin
New Zealand	Starship Childrens Hospital	Auckland
New Zealand	Christchurch Hospital	Christchurch
Switzerland	Kantonsspital Aarau	Aarau
Switzerland	Universitäts-Kinderspital beider	Basel
Switzerland	Ospedale San Giovanni	Bellinzona
Switzerland	Inselspital Bern	Bern
Switzerland	Hug Hopitaux Universitaires De Geneve	Geneve
Switzerland	Centre Hospitalier Universitaire Vaudois Chuv Lausanne	Lausanne
Switzerland	Luzerner Kantonspital - Kinderspital Luzern	Lucerne
Switzerland	Ostschweizer Kinderspital	St. Gallen
Switzerland	University Children's Hospital Zurich	Zurich
United Kingdom	Aberdeen Royal Infirmary, NHS Grampian	Aberdeen
United Kingdom	Royal Aberdeen Children's Hospital	Aberdeen
United Kingdom	Royal Belfast Hospital for Sick Children	Belfast	County Antrim
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	Great Ormond Street Hospital For Children NHS Trust	London
United Kingdom	The Royal Marsden NHS Foundation Trust	London
United Kingdom	University College London Hospitals NHS Foundation 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

Sponsors (5)

Lead Sponsor	Collaborator
University of Birmingham	Assistance Publique - Hôpitaux de Paris, Cancer Research UK, National Cancer Institute, France, Pfizer

Countries where clinical trial is conducted

Australia,  France,  Ireland,  New Zealand,  Switzerland,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Incidence of dose limiting toxicities (DLTs).		Incidence of DLTs will be evaluated up to day 45 post course 1 and course 2 of induction chemotherapy.
Primary	Event Free Survival (EFS).	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.	Event free survival (EFS) will be evaluated as the time from randomisation one to the first event, up to 16 years.
Primary	Event Free Survival (EFS).	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.	Event free survival (EFS) will be evaluated as the time from randomisation two to the first event, up to 16 years..
Primary	Relapse free survival (RFS).	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.	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.
Primary	Early treatment related adverse reactions.	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).	Early treatment related adverse reactions will be evaluated at day 100 post-transplant.
Primary	Relapse free survival (RFS).	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.	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	The nature, incidence and severity of adverse events (AEs) (gemtuzumab ozogamicin dose finding study).		Evaluated by day 45 post course 1 and course 2.
Secondary	Response measured by bone marrow assessment using morphology and minimal residual disease (MRD) assessment (gemtuzumab ozogamicin dose finding study).	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.	Evaluated by day 45 post course 1 and course 2.
Secondary	Serum pharmacokinetic (PK) parameters of gemtuzumab ozogamicin: Clearance (CL) (gemtuzumab ozogamicin dose finding study)	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.	Evaluated up to one month after the first dose of gemtuzumab ozogamicin.
Secondary	Serum pharmacokinetic (PK) parameters of gemtuzumab ozogamicin: Volume of distribution (Vd) (gemtuzumab ozogamicin dose finding study)	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.	Evaluated up to one month after the first dose of gemtuzumab ozogamicin.
Secondary	Complete remission (CR) (R1 & R2).	Evaluated using remission status at completion of course 1 and course 2.	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
Secondary	Reasons for failure to achieve CR (R1 & R2).	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.	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.
Secondary	Cumulative Incidence of Relapse (CIR) (all randomisations).	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.	Evaluated as time from randomisation to the relevant question to relapse, up to 16 years.
Secondary	Death in CR (DCR) (R1, R2 & R3).	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.	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.
Secondary	Event Free Survival (EFS) (R1, R2 & R3).	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.	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.
Secondary	Overall Survival (OS) (all randomisations).	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.	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.
Secondary	Incidence of toxicities (all randomisations).		Evaluated 30 days after end of trial treatment.
Secondary	Incidence of cardiotoxicity (R1, R2 & R4 only).		Evaluated 30 days after end of trial treatment.
Secondary	Incidence of bilirubin of grade 3 of higher (R2 & R4 only).		Evaluated 30 days after end of trial treatment.
Secondary	Incidence of Veno-Occlusive Disease (R2 & R4 only).		Evaluated 30 days after end of trial treatment.
Secondary	Minimal Residual Disease (MRD) clearance after course 1 & 2 (R1 & R2 only).	Evaluated using MRD result at completion of course 1 and 2 once patient's blood counts have recovered or reason for non-recovery has been determined.	Evaluated and presented at completion of course 1 and 2 of treatment, up to a maximum of 45 days post each course of treatment.
Secondary	Time to haematological recovery (all randomisations).	Evaluated using the date of haematological recovery (platelets to >=80 x 10^9/L, and neutrophils to >=1.0 x 10^9/L). The primary analysis will be carried out once the last patient has a minimum of 1 year follow up. Time to haematological recovery estimates will be presented at 45 days post course 1 and course 2 of treatment along with 95% confidence intervals.	Evaluated by day 45 post course 1 and course 2.
Secondary	Days in hospital after each course of treatment (all randomisations).	Total number of days spent in hospital for each course of treatment, collected from date of randomisation until count recovery after final course of treatment, up to a maximum of 45 days post the final course of treatment. This will be summarised per course of treatment.	Evaluated once all patients have completed trial treatment.
Secondary	Incidence of mixed chimerism at day 100 post-transplant (R4 only).		Evaluated at day 100 post-transplant.
Secondary	Treatment Related Mortality (TRM) (R4 only).	The primary analysis will be carried out once the last patient has a minimum of 1 year follow up which is estimated to be 7 years after the start of recruitment. TRM estimates will be presented at 12 months along with 95% confidence intervals.	Evaluated as time in days between randomisation to R4 and death which is unrelated to the underlying disease and considered related to the transplant procedure.
Secondary	Gonadal function (R4 only).	The method of assessment will be by scale (Tanner scale) and physiological parameters. This will be evaluated at 1 year post-transplant and at the end of study follow-up.	Evaluated at 1 year post-transplant and at the end of follow-up, which is estimated to be through to study completion, an average timeframe of 10 years.