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

• Status: Recruiting
• Trial end date: 2032-12-01
• Target enrollment: 0
• Participant gender: All

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.

• Phase: Phase 3
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: University of Birmingham
• Collaborators: Assistance Publique - Hôpitaux de Paris; Cancer Research UK; National Cancer Institute, France; Pfizer
• Treatments: Busulfan; Cyclophosphamide; Cytarabine; Daunorubicin; Fludarabine; Fludarabine phosphate; Gemtuzumab; Mitoxantrone; Vidarabine

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.