Condition category
Cancer
Date applied
03/02/2016
Date assigned
03/02/2016
Last edited
01/11/2017
Prospective/Retrospective
Prospectively registered
Overall trial status
Ongoing
Recruitment status
Recruiting

Contact information

Type

Public

Primary contact

Mr Colin McAlister

ORCID ID

Contact details

Edgbaston
Birmingham
B15 2TT
United Kingdom
+44 121 415 1049
myechild01@trials.bham.ac.uk

Additional identifiers

EudraCT number

2014-005066-30

ClinicalTrials.gov number

NCT02724163

Protocol/serial number

19700

Study information

Scientific 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

Acronym

MyeChild 01

Study hypothesis

Study aims:
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) and cytarabine with liposomal daunorubicin (anthracycline) & cytarabine as induction therapy
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

Ethics approval

Wales REC 3, 27/10/2015, ref: 15/WA/0316

Study design

Randomised; Interventional; Design type: Treatment

Primary study design

Interventional

Secondary study design

Randomised controlled trial

Trial setting

Other

Trial type

Treatment

Patient information sheet

Not available in web format, please use the contact details below to request a patient information sheet

Condition

Topic: Cancer; Subtopic: Haematological Oncology; Disease: Leukaemia (acute myeloid)

Intervention

Randomisation 1
Arm A Induction. Active Comparator: mitoxantrone (mitoxantrone & cytarabine)
Arm B Induction. Experimental: liposomal daunorubicin (liposomal daunorubicin & cytarabine)

Gemtuzumab Ozogamicin Dose Finding Study
Experimental: gemtuzumab ozogamicin (other names: Mylotarg)

Randomisation 3
Arm C Consolidation. Active Comparator: high dose cytarabine.
Arm D Consolidation. Experimental: fludarabine & cytarabine

Randomisation 4
Arm E HSCT. Active Comparator: Myeloablative conditioning (busulfan & cyclophosphamide)
Arm F HSCT. Experimental: Reduced intensity conditioning (busulfan & fludarabine)

Intervention type

Other

Phase

Phase III

Drug names

Primary outcome measures

Gemtuzumab ozogamicin dose finding study:
Incidence of dose limiting toxicities (DLTs) are evaluated up to day 45 post course 1 and course 2 of induction chemotherapy.

Secondary outcome measures

1. Complete remission (R1 and R2) is evaluated and presented after course 1 and 2 or treatment
2. Relapse Free Survival (R3) is determined as time from randomisation 3 to first relapse or death
3. Cumulative Incidence of Relapse (all randomisations) is evaluated as time from randomisation to the relevant question of relapse
4. Days in hospital after each course of treatment (all randomisations) is evaluated once all patients have completed treatment
5. Death in complete remission (R1, R2 and R3) is evaluated as the time from randomisation to date of death from any cause in patients who achieved CR
6. Event Free Survival (R1, R2 and R3) is determined as time from randomisation to the first event
7. Nature, incidence and severity of adverse events (Gemtuzumab ozogamicin dose finding study) are evaluated by day 45 post course 1 and course 2
8. Responses measured by bone marrow assessment (Gemtuzumab ozogamicin dose finding study) on day 21-45 post day 1 of study drugs
9. Event Free Survival (R2) is determined as time from randomisation 2 to the 1st event
10. Gonadal function (R4) is evaluated at 1 year post-transplant and at the end of follow-up
11. Early Treatment Related Adverse Reactions (R4) is measured as incidence by day 100 post-transplant of grade 3-5 toxicity
12. (R4) Relapse Free Survival (R4) is determined as time from Randomisation 4 to the first relapse or death
13. Incidence of bilirubin of grade 3 of higher (R2 and R4) is evaluated 30 days after end of trial treatment
14. Incidence of cardiotoxicity (R1, R2 and R3) is evaluated 30 days after end of trial treatment
15. Incidence of mixed chimerism at day 100 post-transplant (R4) is evaluated at day 100 post-transplant
16. Incidence of toxicities (all randomisations) is evaluated 30 days after end of trial treatment
17. Incidence of Veno-Occlusive Disease(R2 and R4) is evaluated 30 days after end of trial treatment
18. Event Free Survival (R1) is determined as time from randomisation one to the first event
19. Minimal Residual Disease (MRD) clearance after course 1 and 2 (R1 and R2) is evaluated after course 1 and 2 of treatment
20. Overall survival (all randomisations) is determined as time from randomisation to death from any cause or date last seen for patients alive at end of trial
21. Reasons for failure to achieve complete remission (R1 and R2) is evaluated after course 1 and 2 of treatment
22. Clearance and Volume of Distribution (Serum pharmacokinetic parameters of gemtuzumab ozogamicin) at multiple sample time points during course 1
23. Time to haematological recovery (all randomisations) is evaluated by day 45 post course 1 and course 2.;
24. Treatment Related Mortality (R4) is evaluated as time in days between randomisation and death (considered related to the transplant)

Overall trial start date

16/03/2016

Overall trial end date

28/04/2032

Reason abandoned

Eligibility

Participant inclusion criteria

Inclusion criteria for trial entry and Randomisation 1 (induction chemotherapy randomisation):
1. A diagnosis of AML/high risk myelodysplastic syndrome (MDS)/isolated myeloid sarcoma (either de novo or secondary)
2. Aged less than 18 years
3. No prior chemotherapy or biological therapy for AML other than that permitted in the protocol
4. Normal cardiac function (fractional shortening ≥28% or ejection fraction =55%)
5. Fit for protocol chemotherapy
6. Documented negative pregnancy test for female patients of childbearing potential
7. Patient agrees to use effective contraception (patients of childbearing potential)
8. Written informed consent from the patient and/or parent/legal guardian

Inclusion criteria for participation in the gemtuzumab ozogamicin dose finding study:
1. Patients meets the inclusion criteria for trial entry
2. Aged ≥12 months for the major dose finding study
3. Aged ≥12 weeks and 12 months for the minor dose finding study
4. Karnofsky or Lansky performance score of =50
5. Normal renal function defined as calculated creatinine clearance =90ml/min/1.73m2
6. 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
7. ALT or AST =10 x ULN for age
8. Written informed consent from the patient or parent/legal guardian

Inclusion criteria for participation in R3:
1. Patient meets the inclusion criteria for trial entry
2. Induction treatment as per MyeChild 01 protocol or treated with 2 courses of mitoxantrone & cytarabine off trial
3. Minimal residual disease (MRD) response (performed in MyeChild 01 centralised laboratories):
3.1. 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
3.2. 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
4. Written informed consent from the patient and/or parent/legal guardian


Inclusion criteria for participation in R4:
1. Patient meets the eligibility criteria for trial entry
2. Induction treatment as per MyeChild 01 protocol or treated with 1 or 2 courses of mitoxantrone & cytarabine ± treatment intensification with FLA-Ida off trial
3. 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.
4. Patient meets one of the following criteria and is a candidate for haemopoeitic stem cell transplant (HSCT) as per the protocol:
4.1. High risk after course 1 (all patients with poor risk cytogenetics and patients with intermediate risk cytogenetics who fail to achieve CR/CRi)
4.2. 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
4.3. 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 (FLAIda) and after discussion with the Clinical Coordinators
5. 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
6. Written informed consent from the patient or parent/legal guardian

Participant type

Patient

Age group

Child

Gender

Both

Target number of participants

Planned Sample Size: 700; UK Sample Size: 350

Participant exclusion criteria

1. Acute promyelocytic leukaemia (APL)
2. Myeloid leukaemia of Down Syndrome (ML DS)
3. Blast crisis of chronic myeloid leukaemia
4. Relapsed or refractory AML
5. Bone marrow failure syndromes
6. Prior anthracycline exposure which would inhibit the delivery of study anthracyclines
7. Concurrent treatment or administration of any other experimental drug or with any other biological therapy for AML
8. Pregnant or lactating females

Recruitment start date

29/04/2016

Recruitment end date

28/04/2022

Locations

Countries of recruitment

France, Ireland, United Kingdom

Trial participating centre

University of Birmingham
Clinical Trials Unit Edgbaston
Birmingham
B15 2TT
United Kingdom

Sponsor information

Organisation

Cancer Research Clinical Trials Unit (CRCTU)

Sponsor details

Institute of Cancer and Genomic Sciences
University of Birmingham
Edgbaston
Birmingham
B15 2TT
United Kingdom

Sponsor type

University/education

Website

Funders

Funder type

Charity

Funder name

Cancer Research UK

Alternative name(s)

CRUK

Funding Body Type

private sector organisation

Funding Body Subtype

other non-profit

Location

United Kingdom

Results and Publications

Publication and dissemination plan

Not provided at time of registration

Intention to publish date

28/04/2033

Participant level data

Not provided at time of registration

Results - basic reporting

Publication summary

Publication citations

Additional files

Editorial Notes

01/11/2017: Internal review. 25/07/2016: Cancer Help UK lay summary links added. 13/07/2016: Internal review.