| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Children and young adults up to their 18th birthday with newly diagnosed AML, high risk MDS or isolated myeloid sarcoma (MS). |
| Children and young adults up to their 18th birthday with newly diagnosed AML, high risk MDS or isolated myeloid sarcoma (MS). |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| 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 | 20.0 |
| 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) |
|
| 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 |
1. To compare mitoxantrone (anthracenedione) & cytarabine with liposomal daunorubicin (anthracycline) & cytarabine as induction therapy.
2. To compare a single dose of gemtuzumab ozogamicin 3 mg/m2 with the optimum tolerated number of doses of gemtuzumab ozogamicin (identified by the dose-finding study) when combined with induction chemotherapy.
3. To compare two consolidation regimens: high dose cytarabine (HD Ara-C) and fludarabine & cytarabine (FLA) in standard risk patients.
4. To compare the toxicity and efficacy 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. |
1. To compare mitoxantrone (anthracenedione) & cytarabine with liposomal daunorubicin (anthracycline) & cytarabine as induction therapy.
2. To compare a single dose of gemtuzumab ozogamicin 3 mg/m2 with the optimum tolerated number of doses of gemtuzumab ozogamicin (identified by the dose-finding study) when combined with induction chemotherapy.
3. To compare two consolidation regimens: high dose cytarabine (HD Ara-C) and fludarabine & cytarabine (FLA) in standard risk patients.
4. To compare the toxicity and efficacy 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. |
|
| E.2.2 | Secondary objectives of the trial |
1. To compare the predictive value of flow and molecular MRD monitoring for relapse risk.
2. To evaluate a number of prognostic factors with a view to defining a Risk Score for children and adolescents with AML |
1. To compare the predictive value of flow and molecular MRD monitoring for relapse risk.
2. To evaluate a number of prognostic factors with a view to defining a Risk Score for children and adolescents with AML |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Inclusion criteria for trial entry and R1 randomisation
. Diagnosis of AML/high risk MDS (>10% blasts in the bone marrow)/isolated MS
(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 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
Patients with reproductive potential must agree to use effective contraception during the period of therapy. Both men and women of childbearing potential should be advised to use effective contraception to avoid pregnancy up to 12 months after the last dose of study treatment. Effective contraceptive methods include hormonal and barrier contraception etc.
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:
o .12 months for the major dose finding study
o . 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 Gilbertfs 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 (randomisation not yet open)
. Patient meets the inclusion criteria for trial entry (section 4.1.1)
. Age .12 weeks
. 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 and not due to leukaemic involvement or Gilbertfs 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 (section 4.1.1)
. Induction treatment as per MyeChild 01 protocol or treated with 2 courses of mitoxantrone & cytarabine off trial
. 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
o 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 (section 4.1.1)
• 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 HSCT as per the protocol:
o High risk after course 1 (all patients with poor risk cytogenetics and patients with intermediate risk cytogenetics who fail to achieve CR/CRi)
o 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
o 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 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 |
Inclusion criteria for trial entry and R1 randomisation
. Diagnosis of AML/high risk MDS (>10% blasts in the bone marrow)/isolated MS
(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 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
Patients with reproductive potential must agree to use effective contraception during the period of therapy. Both men and women of childbearing potential should be advised to use effective contraception to avoid pregnancy up to 12 months after the last dose of study treatment. Effective contraceptive methods include hormonal and barrier contraception etc.
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:
o .12 months for the major dose finding study
o . 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 Gilbertfs 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 (randomisation not yet open)
. Patient meets the inclusion criteria for trial entry (section 4.1.1)
. Age .12 weeks
. 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 and not due to leukaemic involvement or Gilbertfs 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 (section 4.1.1)
. Induction treatment as per MyeChild 01 protocol or treated with 2 courses of mitoxantrone & cytarabine off trial
. 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
o 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 (section 4.1.1)
• 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 HSCT as per the protocol:
o High risk after course 1 (all patients with poor risk cytogenetics and patients with intermediate risk cytogenetics who fail to achieve CR/CRi)
o 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
o 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 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 |
|
| E.4 | Principal 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
• Pregnant or lactating females |
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
• Pregnant or lactating females |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary outcome
Gemtuzumab Ozogamicin Dose Finding Study
• The incidence of dose limiting toxicities (DLTs)
Randomisation 1: Induction Randomisation (R1)
• EFS from date of randomisation 1(R1)
Randomisation 2: Gemtuzumab Ozogamicin Randomisation (R2)
• EFS from date of randomisation 2 (R2)
Randomisation 3: Consolidation Randomisation (R3)
• RFS from date of randomisation 3 (R3)
Randomisation 4: HSCT Conditioning Randomisation (R4)
• Early treatment related adverse events (AEs)
• RFS from date of randomisation 4 (R4)
Secondary outcole
Gemtuzumab Ozogamicin Dose Finding Study
• The nature, incidence and severity of AEs
• Responses measured by bone marrow assessment using morphology and MRD assessment between day 21-45 post day 1 of induction therapy.
• Serum Pharmacokinetic (PK) parameters of gemtuzumab ozogamicin : CL and Vd
All randomisations
• CR (R1 and R2 only)
• Reasons for failure to achieve CR (R1 and R2 only)
Protocol
MyeChild 01Protocol
V1.0a, 04-Aug-2015
Page 34 of 130
MyeChild 01
• CIR
• Death in CR (DCR)
• EFS
• OS
• Incidence of toxicities
• Incidence of cardiotoxicity (R1, R2 and R4 only)
• Incidence of bilirubin of grade 3 or higher (R2 and R4 only)
• Incidence of VOD (R2 and R4 only)
• MRD clearance after course 1 and course 2 and MRD negativity post-therapy (R1 and R2 only)
• Time to haematological recovery
• Days in hospital after each course of treatment
• Incidence of mixed chimerism at day 100 post-transplant (R4 only)
• TRM (R4 only)
• Gonadal function at 1 year post-transplant and end of study follow up (R4 only) |
Primary outcome
Gemtuzumab Ozogamicin Dose Finding Study
• The incidence of dose limiting toxicities (DLTs)
Randomisation 1: Induction Randomisation (R1)
• EFS from date of randomisation 1(R1)
Randomisation 2: Gemtuzumab Ozogamicin Randomisation (R2)
• EFS from date of randomisation 2 (R2)
Randomisation 3: Consolidation Randomisation (R3)
• RFS from date of randomisation 3 (R3)
Randomisation 4: HSCT Conditioning Randomisation (R4)
• Early treatment related adverse events (AEs)
• RFS from date of randomisation 4 (R4)
Secondary outcole
Gemtuzumab Ozogamicin Dose Finding Study
• The nature, incidence and severity of AEs
• Responses measured by bone marrow assessment using morphology and MRD assessment between day 21-45 post day 1 of induction therapy.
• Serum Pharmacokinetic (PK) parameters of gemtuzumab ozogamicin : CL and Vd
All randomisations
• CR (R1 and R2 only)
• Reasons for failure to achieve CR (R1 and R2 only)
Protocol
MyeChild 01Protocol
V1.0a, 04-Aug-2015
Page 34 of 130
MyeChild 01
• CIR
• Death in CR (DCR)
• EFS
• OS
• Incidence of toxicities
• Incidence of cardiotoxicity (R1, R2 and R4 only)
• Incidence of bilirubin of grade 3 or higher (R2 and R4 only)
• Incidence of VOD (R2 and R4 only)
• MRD clearance after course 1 and course 2 and MRD negativity post-therapy (R1 and R2 only)
• Time to haematological recovery
• Days in hospital after each course of treatment
• Incidence of mixed chimerism at day 100 post-transplant (R4 only)
• TRM (R4 only)
• Gonadal function at 1 year post-transplant and end of study follow up (R4 only) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
1. To compare the predictive value of flow and molecular MRD monitoring for relapse risk.
2. To evaluate a number of prognostic factors with a view to defining a Risk Score for children and adolescents with AML |
1. To compare the predictive value of flow and molecular MRD monitoring for relapse risk.
2. To evaluate a number of prognostic factors with a view to defining a Risk Score for children and adolescents with AML |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | No |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| 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) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| 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 | Yes |
| 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.8.3 |
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 | 28 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 0 |
| 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 | Yes |
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 7 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 10 |
| 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 | 0 |
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