Clinical trial NCT02724163: International Randomised Phase III Clinical Trial in Children With Acute Myeloid Leukaemia
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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Acute Myeloid Leukaemia
Keywords: Acute Myeloid Leukaemia
Children
Gemtuzumab ozogamicin
Liposomal daunorubicin
Mitoxantrone
Randomised controlled trial
Risk stratification
Minimal residual disease
Stem cell transplant
Lead sponsor: University of Birmingham
Sponsor class: OTHER
Collaborators: name: Assistance Publique - Hôpitaux de Paris
name: Cancer Research UK
name: National Cancer Institute, France
name: Pfizer
First posted: 2016-03-31
Enrollment: 700
Sex: ALL
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Incidence of dose limiting toxicities (DLTs).
timeFrame: Incidence of DLTs will be evaluated up to day 45 post course 1 and course 2 of induction chemotherapy.
measure: Event Free Survival (EFS).
timeFrame: Event free survival (EFS) will be evaluated as the time from randomisation one to the first event, up to 16 years.
measure: Event Free Survival (EFS).
timeFrame: Event free survival (EFS) will be evaluated as the time from randomisation two to the first event, up to 16 years..
measure: Relapse free survival (RFS).
timeFrame: 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.
measure: Early treatment related adverse reactions.
timeFrame: Early treatment related adverse reactions will be evaluated at day 100 post-transplant.
measure: Relapse free survival (RFS).
timeFrame: 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).
timeFrame: Evaluated by day 45 post course 1 and course 2.
measure: Response measured by bone marrow assessment using morphology and minimal residual disease (MRD) assessment (gemtuzumab ozogamicin dose finding study).
timeFrame: Evaluated by day 45 post course 1 and course 2.
measure: Serum pharmacokinetic (PK) parameters of gemtuzumab ozogamicin: Clearance (CL) (gemtuzumab ozogamicin dose finding study)
timeFrame: Evaluated up to one month after the first dose of gemtuzumab ozogamicin.
measure: Serum pharmacokinetic (PK) parameters of gemtuzumab ozogamicin: Volume of distribution (Vd) (gemtuzumab ozogamicin dose finding study)
timeFrame: Evaluated up to one month after the first dose of gemtuzumab ozogamicin.
measure: Complete remission (CR) (R1 & R2).
timeFrame: 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
measure: Reasons for failure to achieve CR (R1 & R2).
timeFrame: 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.
measure: Cumulative Incidence of Relapse (CIR) (all randomisations).
timeFrame: Evaluated as time from randomisation to the relevant question to relapse, up to 16 years.
measure: Death in CR (DCR) (R1, R2 & R3).
timeFrame: 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.
measure: Event Free Survival (EFS) (R1, R2 & R3).
timeFrame: 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.
measure: Overall Survival (OS) (all randomisations).
timeFrame: 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).
timeFrame: Evaluated 30 days after end of trial treatment.
measure: Incidence of cardiotoxicity (R1, R2 & R4 only).
timeFrame: Evaluated 30 days after end of trial treatment.
measure: Incidence of bilirubin of grade 3 of higher (R2 & R4 only).
timeFrame: Evaluated 30 days after end of trial treatment.
measure: Incidence of Veno-Occlusive Disease (R2 & R4 only).
timeFrame: Evaluated 30 days after end of trial treatment.
measure: Minimal Residual Disease (MRD) clearance after course 1 & 2 (R1 & R2 only).
timeFrame: Evaluated and presented at completion of course 1 and 2 of treatment, up to a maximum of 45 days post each course of treatment.
measure: Time to haematological recovery (all randomisations).
timeFrame: Evaluated by day 45 post course 1 and course 2.
measure: Days in hospital after each course of treatment (all randomisations).
timeFrame: Evaluated once all patients have completed trial treatment.
measure: Incidence of mixed chimerism at day 100 post-transplant (R4 only).
timeFrame: Evaluated at day 100 post-transplant.
measure: Treatment Related Mortality (TRM) (R4 only).
timeFrame: 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.
measure: Gonadal function (R4 only).
timeFrame: 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.
Other outcomes:
Locations:
city: Adelaide
country: Australia
facility: Women and Children's Hospital Adelaide
city: Brisbane
country: Australia
facility: Queensland Children's Hospital
city: Melbourne
country: Australia
facility: Monash Children's Hospital
city: Melbourne
country: Australia
facility: Royal Childrens Hospital
city: New Lambton Heights
country: Australia
facility: John Hunter Children's Hopsital
city: Perth
country: Australia
facility: Perth Children's Hospital
city: Sydney
country: Australia
facility: Sydney Children's Hospital
city: Westmead
country: Australia
facility: The Childrens Hospital At Westmead
city: Amiens
country: France
facility: Centre Hospitalier Universitaire Amiens - Picardie
city: Angers
country: France
facility: Centre Hospitalier Universitaire D'angers
city: Besançon
country: France
facility: Centre Hospitalier Regional Universitaire Besancon - Hopital Jean Minjoz
city: Bordeaux
country: France
facility: Centre Hospitalier Universitaire De Bordeaux - Hopital Pellegrin
city: Brest
country: France
facility: Centre Hospitalier Regional Universitaire Brest - Hopital Morvan
city: Caen
country: France
facility: Centre Hospitalier Universitaire De Caen
city: Clermont-Ferrand
country: France
facility: Centre Hospitalier Universitaire De Clermont-ferrand
city: Dijon
country: France
facility: Centre Hospitalier Universitaire Dijon Bourgogne - Hopital D'enfants
city: Grenoble
country: France
facility: Centre Hospitalier Universitaire De Grenoble
city: Lille
country: France
facility: Hopital Jeanne Dr Flandre
city: Limoges
country: France
facility: Centre Hospitalier Universitaire De Limoges
city: Lyon
country: France
facility: Centre Leon Berard
city: Marseille
country: France
facility: Hopital De La Timone
city: Montpellier
country: France
facility: Centre Hospitalier Regional Universitaire Montpellier - Hopital Arnaud-de-villeneuve
city: Nancy
country: France
facility: Centre Hospitalier Universitaire De Nancy
city: Nantes
country: France
facility: Centre Hospitalier Universitaire De Nantes
city: Nice
country: France
facility: Centre Hospitalier Universitaire De NICE
city: Paris
country: France
facility: Hopital Armand Trousseau
city: Paris
country: France
facility: Hopital Robert Debre
city: Paris
country: France
facility: Hopital Saint Louis
city: Poitiers
country: France
facility: Centre Hospitalier Universitaire De Poitiers
city: Reims
country: France
facility: Chu De Reims
city: Rennes
country: France
facility: Centre Hospitalier Universitaire De Rennes - Hopital Sud
city: Rouen
country: France
facility: Centre Hospitalier Universitaire De Rouen
city: Saint-Étienne
country: France
facility: Centre Hospitalier Universitaire Saint-etienne
city: Strasbourg
country: France
facility: Strasbourg Hautepierre
city: Toulouse
country: France
facility: Centre Hospitalier Universitaire De Toulouse - Hopital Des Enfants
city: Tours
country: France
facility: Centre Hospitalier Regional Universitaire De Tours - Hopital Clocheville
city: Dublin
country: Ireland
facility: Our Lady's Hospital for Sick Children
city: Auckland
country: New Zealand
facility: Starship Childrens Hospital
city: Christchurch
country: New Zealand
facility: Christchurch Hospital
city: Aarau
country: Switzerland
facility: Kantonsspital Aarau
city: Basel
country: Switzerland
facility: Universitäts-Kinderspital beider
city: Bellinzona
country: Switzerland
facility: Ospedale San Giovanni
city: Bern
country: Switzerland
facility: Inselspital Bern
city: Geneve
country: Switzerland
facility: Hug Hopitaux Universitaires De Geneve
city: Lausanne
country: Switzerland
facility: Centre Hospitalier Universitaire Vaudois Chuv Lausanne
city: Lucerne
country: Switzerland
facility: Luzerner Kantonspital - Kinderspital Luzern
city: St. Gallen
country: Switzerland
facility: Ostschweizer Kinderspital
city: Zurich
country: Switzerland
facility: University Children's Hospital Zurich
city: Belfast
country: United Kingdom
facility: Royal Belfast Hospital for Sick Children
state: County Antrim
city: Aberdeen
country: United Kingdom
facility: Royal Aberdeen Children's Hospital
city: Aberdeen
country: United Kingdom
facility: Aberdeen Royal Infirmary, NHS Grampian
city: Birmingham
country: United Kingdom
facility: Birmingham Children's Hospital NHS Foundation Trust
city: Bristol
country: United Kingdom
facility: University Hospitals Bristol NHS Foundation Trust
city: Cambridge
country: United Kingdom
facility: Addenbrookes Hospital, Cambridge University Hospitals NHS Foundation Trust
city: Cardiff
country: United Kingdom
facility: Cardiff and Vale University Health Board, Noah's Ark Children's Hospital for Wales
city: Edinburgh
country: United Kingdom
facility: NHS Lothian, Royal Hospital for Sick Children
city: Glasgow
country: United Kingdom
facility: NHS Greater Glasgow and Clyde, The Royal Hospital for Children
city: Leeds
country: United Kingdom
facility: Leeds General Infirmary, Leeds Teaching Hospitals NHS Trust
city: Liverpool
country: United Kingdom
facility: Alder Hey Children's NHS Foundation Trust
city: London
country: United Kingdom
facility: University College London Hospitals NHS Foundation Trust
city: London
country: United Kingdom
facility: The Royal Marsden NHS Foundation Trust
city: London
country: United Kingdom
facility: Great Ormond Street Hospital For Children NHS Trust
city: Manchester
country: United Kingdom
facility: Royal Manchester Childrens' Hospital , Central Manchester University Hospitals NHS Foundation Trust
city: Newcastle
country: United Kingdom
facility: The Newcastle Upon Tyne Hospitals NHS Foundation Trust
city: Nottingham
country: United Kingdom
facility: Nottingham University Hospitals NHS Trust
city: Oxford
country: United Kingdom
facility: John Radcliffe Hospital, Oxford Radcliffe Hospitals NHS Trust
city: Sheffield
country: United Kingdom
facility: Sheffield Children's NHS Foundation Trust
city: Southampton
country: United Kingdom
facility: Southampton University Hospitals NHS Trust
Study officials:
affiliation: Royal Hospital for Children Glasgow
name: Brenda Gibson
role: PRINCIPAL_INVESTIGATOR
References: