| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
| A serious malignant blood disorder which is fatal if not treated. |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 18.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10000880 |
| E.1.2 | Term | Acute myeloid leukaemia |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
There are several principal research objectives, all in either newly diagnosed acute myeloid leukaemia (AML) or high risk myelodysplastic syndrome(MDS):
- To compare mitoxantrone and cytarabine with liposomal daunorubicin and cytarabine as induction chemotherapy.
- To establish the optimum tolerated number of 3mg/m2 doses of gemtuzumab ozogamicin (up to a maximum of 3 doses) that can be safely delivered in combination with protocol induction chemotherapy (mitoxantrone and cytarabine, and liposomal daunorubicin and cytarabine).
- To compare a single dose of gemtuzumab ozogamicin 3mg/m2 with the optimum tolerated number of doses (identified by the previous objective) when combined with induction chemotherapy.
- To compare two consolidation regimens: high dose cytarabine vs fludarabine and cytarabine (FLA) in standard risk patients
- To compare the toxicity and efficacy of two haemopoietic stem cell transplant (HSCT) conditioning regimens of different intensity: conven |
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| E.2.2 | Secondary objectives of the trial |
The secondary research objectives are:
- To compare two methods of measuring and monitoring minimal residual disease (MRD) levels: flow cytometry versus molecular methods, to see if one is better at predicting relapse
- To evaluate a number of prognostic factors with a view to define a risk score for children and adolescents with AML |
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| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
1) Liposomal Duanorubicin and Mitoxantrone Pharmacokinetic Sub-study. The objectives are:
a. To investigate inter-individual variability in the PKs of liposomal daunorubicin and mitoxantrone in infants and young children with AML receiving reduced dosing regimens
b. To compare drug exposures and degree of PK variability in infants and young children receiving reduced dosing regimens with data obtained from older children receiving standard doses
c. To relate inter-individual variability in PKs and drug exposure to clinical toxicity and response
d. To use PK data in conjunction with clinical information obtained following treatment to investigate the suitability of current dosing regimens for liposomal daunorubicin and mitoxantrone in infants and young children
2) Genetic and Functional Leukaemic Stem Cell Studies in Paediatric AML. The objectives of this study are:
a. To track leukaemic stem cell (LSC) populations functionally through xenograft assays and quantitate LSC populations by flow cytometry
b. To compare the relative sensitivity of flow-cytometry leukaemia-aberrant phenotype MRD with flow cytometric LSC-detection based MRD and molecular MRD
c. To investigate whether LSC populations are more chemoresistant and valuable to monitor clinically
d. To study clonal structures in LSC populations from diagnosis, through treatment and after therapy and in relapse to understand which LSC clones are chemoresistant
3) Transcriptome Sequencing in Childhood AML. The objectives of this study are:
a. To determine the types and incidences of known and novel genetic rearrangements and mutations within childhood AML through their study within a complete clinical trial
b. Transcriptome sequencing of the whole genome will identify known and novel mutations from which their involvement in specific signalling pathways and their functional roles can be elucidated.
c. To examine the relationship of novel genetic abnormalities to other genetic changes of known prognostic relevance, which will be well annotated within this trial cohort.
d. To determine whether they have an impact on the outcome that is predicted from other features of risk stratification
e. To determine whether specific combinations of abnormalities will impact on outcome within the different genetic subgroups
f. To investigate the identified molecular markers as target for MRD detection
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| E.3 | Principal inclusion criteria |
Inclusion criteria for trial entry and Randomisation 1 (induction chemotherapy randomisation):
- A diagnosis of AML/high risk myelodysplastic syndrome (MDS)/isolated myeloid sarcoma (either de novo or secondary)
- Age <18 years
- No prior chemotherapy or biological therapy for AML other than that permitted in the protocol
- Normal cardiac function (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 childbearing potential)
- Written informed consent from the patient and/or parent/legal guardian
Inclusion criteria for participation in the gemtuzumab ozogamicin dose finding study:
- Patients meets the inclusion criteria for trial entry
- Age ≥12 months for the major dose finding study
- Age ≥ 12 weeks and <12 months for the minor dose finding study
- Karnofsky or Lansky performance score of ≥50
- 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
- ALT or AST ≤10 x ULN for age
- Written informed consent from the patient 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):
1) 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
2) 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 eligibility criteria for trial entry
- Induction treatment as per MyeChild 01 protocol or treated with 1 or 2 courses of mitoxantrone & cytarabine ± treatment intensification with FLA-Ida off trial
- Patient is in CR or 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 haemopoeitic stem cell transplant (HSCT) as per the protocol:
1) High risk after course 1 (all patients with poor risk cytogenetics and patients with intermediate risk cytogenetics who fail to achieve CR/CRi)
2) 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
3) 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 or parent/legal guardian
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| E.4 | Principal exclusion criteria |
Exclusion criteria for all randomisations
- Acute promyelocytic leukaemia (APL)
- Myeloid leukaemia of Down Syndrome (ML DS)
- 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
- Pregnant or lactating females
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary outcome measure for the gemtuzumab ozogamicin dose finding study is incidence of dose limiting toxicities (DLTs).
The primary outcome measure for randomisation 1: induction randomisation (R1) is event free survival (EFS).
The primary outcome for randomisation 2: gemtuzumab ozogamicin randomisation (R2) is EFS.
The primary outcome measure for randomisation 3: consolidation randomisation (R3) is relapse free survival (RFS).
The primary outcomes for randomisation 4: haemopoietic stem cell transplant conditioning randomisation (R4) are:
1) 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/typhilitis/upper and lower GI haemorrhage)
- Investigations (bilirubin)
- Renal and Urinary (acute kidney injury/haematuria)
- Nervous system(seizure)
2) RFS
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Gemtuzumab ozogamicin dose finding study: Incidence of dose limiting toxicities (DLTs) will be evaluated up to day 45 post course 1 and course 2 of induction chemotherapy.
R1: Event free survival (EFS) will be evaluated as the time from randomisation (R1) to the first event.
R2: EFS will be evaluated as the time from randomisation (R2) to the first event.
R3: Relapse free survival (RFS) will be evaluated as the time of randomisation (R3) to the first relapse or death from any cause.
R4: Early treatment related adverse reactions will be evaluated at day 100 post-transplant. RFS will be evaluated as the time from randomisation to the first of relapse or death from any cause.
The primary analysis will be carried out once the last patient has a minimum of 1 year follow up. |
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| E.5.2 | Secondary end point(s) |
Secondary outcome measures for the gemtuzumab ozogamicin dose finding study are:
The nature, incidence and severity of adverse events (AEs)
Response measured by bone marrow morphology and MRD assessment
Serum pharmacokinetic parameters of gemtuzumab ozogamicin
Secondary outcome measures for randomisations:
Complete remission (CR) (R1 and R2)
Reasons for failure to achieve CR (R1 and R2)
Cumulative incidence of relapse (all randomisations)
Death in CR (R1, R2 and R3)
Event free survival (EFS) (R1, R2 and R3)
Overall survival (OS) (all randomisations)
Incidence of toxicities (all randomisations)
Incidence of cardiotoxicity (R1, R2 and R4)
Incidence of bilirubin of grade 3 or higher (R2 and R4)
Incidence of veno-occlusive disease (R2 and R4)
MRD clearance after course 1 and course 2 and MRD negativity post-therapy (R1 and R2)
Time to haematological recovery (all randomisations)
Days in hospital after each course of treatment (all randomisations)
Incidence of mixed chimerism at day 100 post-transplant (R4)
Treatment related mortality (R4)
Gonadal function at 1 year post-transplant and end of study follow up (R4) |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Rate of haematological recovery will be evaluated by day 45 post course 1 and course 2
Days in hospital per course of treatment will be evaluated at the end of treatment
Incidence of mixed chimerism will be evaluated at day 100 post-transplant
Gonadal function will be evaluated 1 year post-transplant and at the end of follow up
The following will be evaluated after course 1 and 2:
Complete remission (CR)
Reason for failure to achieve CR
MRD clearance and MRD negativity
The following will be evaluated 30 days after end of trial treatment:
Toxicity
Cardiotoxicity (and at end of follow up)
Bilirubin
VOD
The following will be evaluated on a time to event basis:
Cumulative incidence of relapse (CIR)
Death in CR
Event free survival
Overall survival
Transplant related mortality |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
|
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 8 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 19 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 3 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
The end of trial will be 12 months after the last data capture. This will allow sufficient time for the completion of protocol procedures, data collection input and cleaning of data.
The relevant national coordinating centre (NCC) will notify the relevant Competent Authority and Ethics Committee that the trial has ended at the appropriate time and will provide them with a summary of the clinical trial report within 6 months of the declaration of the end of trial.
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 17 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 1 |
| E.8.9.2 | In all countries concerned by the trial years | 17 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 1 |
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