Myechild 01: 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

Overview

Sponsor-declared trial summary

Key facts

Sponsor

The University Of Birmingham

Participant type

Pediatric, Patients

Age range

0-17 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

20 Nov 2017 → ongoing

Decision date (initial)

2024-12-02

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Cancer Research UK · Direction Generale de l'Offre de Soins (DGOS) · Pfizer · Galen Limited

External identifiers

EU CT number

2024-516112-21-00

EudraCT number

2014-005066-30

ClinicalTrials.gov

NCT02724163

ISRCTN

ISRCTN12389567

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Therapy, Pharmacokinetic, Efficacy, Pharmacodynamic

In newly diagnosed AML, high risk MDS (>10% blasts in the bone marrow) and isolated myeloid sarcoma:

Embedded dose finding studies
- To establish the optimum tolerated number of 3 mg/m2 doses of gemtuzumab ozogamicin (up to a maximum of 3 doses) that can be safely delivered in combination with cytarabine plus mitoxantrone or liposomal daunorubicin in induction

Randomised
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 myeloablaive conditioning (MAC) with busulfan/cyclophosphamide and reduced intensity conditioning (RIC) with fludarabine/busulfan.

Secondary objectives 2

1. To compare the predictive value of flow and molecular minimal residual disease (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.

Conditions and MedDRA coding

Newly diagnosed acute myeloid leukaemia (AML), high risk myelodysplastic syndrome (MDS) and isolated myeloid sarcoma (either de novo or secondary)

Regulatory references

EMA paediatric investigation plan (PIP)

EMEA-001733-PIP02-15

Plan to share IPD

Yes

IPD plan description

The data generated by this trial will be analysed by the trial statistician, at the CRCTU, University of Birmingham. Following completion of the gemtuzumab ozogamicin dose finding study and the Randomisation 2, the data from this part of the trial will be shared with Pfizer, who are based in the United States. The data will be sent in an anonymised form. Pfizer may use this data as part of a licensing application. Access to trial data is controlled through application to the CRCTU New Business Committee and is granted in accordance with the CRCTU Data Sharing Policy.

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 36

1. Trial Entry & R1 : A 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)
2. Dose Finding Study: Patient meets the inclusion criteria for Trial Entry & R1
3. Dose Finding Study: Age: ≥12 months for the major dose finding study OR ≥ 12 weeks and <12 months for the minor dose finding study
4. Dose Finding Study: Normal renal function defined as calculated creatinine clearance ≥90ml/min/1.73m2
5. Dose Finding Study: 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
6. Dose Finding Study: ALT or AST ≤10 x ULN for age
7. Dose Finding Study: Written informed consent from the patient and/or parent/legal guardian
8. Gemtuzumab ozogamicin not as part of DFS or R2: Patient meets the inclusion criteria for Trial Entry & R1
9. Gemtuzumab ozogamicin not as part of DFS or R2: Age: ≥12 months OR ≥ 12 weeks OR ≥28 days and <12 weeks (patients will receive a maximum of one dose of gemtuzumab ozogamicin)
10. Gemtuzumab ozogamicin not as part of DFS or R2: Normal renal function, defined as calculated creatinine clearance ≥90 ml/min/1.73m2
11. Gemtuzumab ozogamicin not as part of DFS or R2: 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
12. Trial Entry & R1: Age <18 years at trial entry
13. Gemtuzumab ozogamicin not as part of DFS or R2: ALT or AST ≤10 x ULN for age
14. Gemtuzumab ozogamicin not as part of DFS or R2: Written informed consent from the patient and/or parent/legal guardian
15. R2: Patient meets the inclusion criteria for Trial Entry & R1
16. R2: Patient age: ≥12 months OR ≥12 weeks (once R2 open in patients aged ≥12 weeks and <12 months)
17. R2: Normal renal function defined as calculated creatinine clearance ≥90ml/min/1.73m2
18. R2: 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
19. R2: ALT or AST ≤10 x ULN for age
20. R2: Written informed consent from the patient and/or parent/legal guardian
21. R3: Patient meets the inclusion criteria for Trial Entry & R1
22. R3: Induction treatment as per MyeChild 01 protocol or treated with 2 courses of mitoxantrone & cytarabine off trial
23. Trial Entry & R1: No prior chemotherapy or biological therapy for AML/high risk MDS/isolated MS other than that permitted in the protocol
24. R3: MRD response: 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
25. R3: Written informed consent from the patient and/or parent/legal guardian
26. R4: Patient meets the inclusion criteria for Trial Entry & R1
27. R4: Induction treatment as per MyeChild 01 protocol or treated with 1 or 2 courses of mitoxantrone & cytarabine ± treatment intensification with FLA-Ida off trial
28. R4: 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
29. 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) OR 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 OR Good risk cytogenetics with flow MRD >0.1% or 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
30. R4: 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
31. R4: Written informed consent from the patient and/or parent/legal guardian
32. Trial Entry & R1: Normal cardiac function defined as fractional shortening ≥28% or ejection fraction ≥55%
33. Trial Entry & R1: Fit for protocol chemotherapy
34. Trial Entry & R1: Documented negative pregnancy test for female patients of childbearing potential
35. Trial Entry & R1: Written informed consent from the patient and/or parent/legal guardian
36. Trial Entry & R1: 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.

Exclusion criteria 8

1. Acute Promyelocytic Leukaemia
2. Down Syndrome
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/high risk MDS/isolated MS
8. Pregnant or lactating females

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 6

1. Dose Finding Study: The incidence of dose limiting toxicities (DLTs)
2. R1: Event-free survival (EFS) from date of randomisation 1 (R1)
3. R2: Event-free survival (EFS) from date of randomisation 2 (R2)
4. R3: Relapse-free survival (RFS) from date of randomisation 3 (R3)
5. R4: Early treatment related adverse reactions defined as the incidence by day 100 post-transplant of grade 3-5 toxicity for specific toxicities in the following systems using the National Cancer Institute (NCI) Common Terminology Criteria v4: Cardiac; Respiratory, thoracic and mediastinal; Gastrointestinal; Investigations; Renal and Urinary; Nervous system
6. R4: Relapse-free survival (RFS) from date of randomisation 4 (R4)

Secondary endpoints 17

1. Dose Finding Study: The nature, incidence and severity of AEs evaluated until day 45 post course 1 and course 2
2. Dose Finding Study: Response measured by bone marrow morphology and MRD assessment post course 1 and 2
3. Complete Remission (CR) defined as CR or CRi and evaluated post course 1 and 2 of treatment (R1 and R2 only)
4. Reasons for failure to achieve CR evaluated pose course 1 and 2 of treatment and classified as resistant disease, induction death or not evaluable (R1 and R2 only)
5. Cumulative incidence of relapse (CIR) defined as time from first CR or CRi for patients entering at induction or from randomisation to the relevant question for patients entering at R3 or R4, to relapse
6. Death in CR (DCR) defined as time from first CR or CRi for patients entering at induction or from randomisation to the relevant question for patients entering at R3 or R4, to date of death from any cause.
7. Event-free survival defined 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.
8. Overall Survival (OS) defined 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
9. Incidence of cardiotoxicity experienced within 10 years of randomisation and defined as a fall in fractional shortening to <28% or ejection fraction <55% (R1, R2 and R4 only)
10. Incidence of bilirubin of grade 3 or higher experienced within 30 days of end of trial treatment (R2 and R4 only)
11. Incidence of veno-occlusive disease experienced within 30 days of end of trial treatment (R2 and R4 only)
12. MRD negativity post course 1, course 2 and at the end of treatment (R1 and R2 only)
13. Time to haematological recovery defined as time from start of course to date of neutrophil recovery to 1.0 x 10^9/L and platelet recovery to 80 x 10^9/L for DFS patients; and neutrophil recover to 0.75 x 10^9/L and platelet recovery to 75 x 10^9/L for all other patients
14. Days in hospital per course of treatment
15. Incidence of mixed chimerism at day 100 post-transplant (R4 only)
16. Treatment Related Mortality (TRM) defined as the time bwtween randomisation to R4 and death which is unrelated to the underlying disease and considered related to the transplant procedure (R4 only)
17. Gonadal function at 1 year post-transplant and end of study follow up, assessed by Tanner stage, gonadotrophins and serum AMH (females)/inhibin B (males) (R4 only)

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 4

Comparator 8

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

The University Of Birmingham

Sponsor organisation

The University Of Birmingham

Address

Vincent Drive

City

Birmingham

Postcode

B15 2TT

Country

United Kingdom

Scientific contact point

Organisation

The University Of Birmingham

Contact name

Clinical Trial Coordinator

Public contact point

Organisation

The University Of Birmingham

Contact name

Clinical Trial Coordinator

Third parties 7

Locations

2 EU/EEA countries · 29 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 75 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

1 submissions — initial application plus substantial / non-substantial modifications