CHIP-AML22 Master protocol: Protocol for the treatment of children and adolescents with Acute Myeloid Leukemia (AML)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Prinses Maxima Centrum voor Kinderoncologie B.V.

Participant type

Pediatric, Patients

Age range

0-17 years, 18-64 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

14 Jul 2023 → ongoing

Decision date (initial)

2024-07-15

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

EUROPEAN COMMISSION

External identifiers

EU CT number

2023-504999-25-00

EudraCT number

2022-002885-34

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety, Therapy

• Overarching objective:
To improve the overall EFS for children and adolescents with newly diagnosed AML, compared to NOPHO-DBH AML-2012.
• Induction randomization:
To assess if adding GO to the first induction course results in better early anti-leukemic efficacy in CD33-positive AML patients, compared to no-GO.
• Consolidation randomization:
To demonstrate non-inferiority in disease-free survival of two courses of consolidation therapy, by omitting HA3E, as compared to three courses, in the entire standard-risk group eligible for this randomization.

Secondary objectives 3

1. Entire study population: o To improve short-term efficacy by different endpoints, overall survival (OS), disease-free survival (DFS) and the cumulative incidence of relapse (CIR) o To decrease treatment-related toxicity.
2. Induction randomization: • To evaluate differences in anti-leukemic efficacy in the total group, in both arms, and among subgroups as defined by the intensity of CD33-expression, CD33 SNPs, and cytogenetics. • To assess the safety of adding GO to induction course 1, compared to no-GO.
3. Consolidation randomization: o To improve safety of consolidation treatment. o To compare consumption of health-care resources o To compare overall survival (OS) and the cumulative incidence of relapse (CIR)

Conditions and MedDRA coding

Acute Myeloid Leukemia

Study design 2 periods

Regulatory references

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 6

1. Newly diagnosed AML. The origin of AML must be de novo (not secondary to bone marrow failure or therapy-related).
2. Age ≥1 day and ≤ 18 years old at initial diagnosis.
3. Written informed consent/assent from patients and/or from parents or legal guardians for minor patients, according to local law and regulations.
4. Able to comply with scheduled follow-up and with management of toxicity.
5. Additional inclusion criteria for the induction randomization: 1) CD33 positivity of leukemic blasts as measured by flow cytometry (mean fluorescence intensity; MFI) at diagnosis (bone marrow aspirate and/or peripheral blood). CD33 positivity is defined as a ratio of at least 10 (using the anti-CD33 clone P67.6) of the geometric MFI of CD33 for the ‘blast population’ divided by the MFI of the CD33 background signal of lymphocytes. 2) Informed consent for participation in randomization Ri.
6. Additional inclusion criteria for the consolidation randomization 1) Patients included in the CHIP-AML22 protocol and stratified to Standard Risk Group according to the stratification algorithm of the protocol. 2) Informed consent for participation in randomization Rc.

Exclusion criteria 16

1. Previous chemotherapy or radiotherapy. This includes patient with therapy-related AML after previous therapy that is known to increase the risk of secondary AML.
2. Myelodysplastic syndrome (MDS).
3. Juvenile Myelomonocytic Leukemia (JMML).
4. Known intolerance to any of the chemotherapeutic drugs in the protocol.
5. Evidence of cardiac dysfunction (ejection fraction below 50%, or between 50% and 55% and considered as left ventricular systolic dysfunction by the local (pediatric) cardiologist).
6. Pregnant or lactating patients, or sexually active female patients of childbearing potential not willing to use a highly effective method of contraception and, if indicated, monthly pregnancy testing for the duration of study therapy and up to 7 months after the completion of all study therapy.
7. Additional exclusion criteria for the induction randomization: 1) Hypersensitivity to the active substance of GO or to any of the excipients listed in section 6.1 of the SPC of GO. 2) Patients with FLT3-ITD/NPM1wt. 3) Elevated bilirubin ≥ grade 3 according to the CTCAE v5.0.
8. Sexually active, fertile male patients, not willing to use an effective method of contraception, for the duration of study therapy, and up to 6 months after the completion of all study therapy.
9. Concomitant administration of any other experimental drug, or concurrent treatment with any other anti-cancer therapy other than specified in this protocol or in one of the trials linked to this Master protocol, when the study objective is affected.
10. Patients who in the opinion of the investigator, may not be able to comply with the study requirements of the study.
11. Patients with known active hepatitis B, hepatitis C, or HIV infection.
12. Patients for whom informed consent was not obtained.
13. Patients with a (known) germline predisposition for bone marrow failure, like Fanconi anemia.
14. Myeloid Leukemia of Down syndrome (MLDS).
15. Acute promyelocytic leukemia (APL).
16. Additional exclusion criteria for consolidation randomization 1) Patients who previously did not receive chemotherapy according to protocol.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 3

1. Primary endpoint of overarching objective: Event-free survival (EFS)
2. Primary end point induction Randomization: • MRD <0.1% leukemic cells in the BM, as defined by flow cytometry, shortly before start of induction course 2 (BM1).
3. Primary endpoint of consolidation Randomization: Disease-Free Survival (DFS)

Secondary endpoints 8

1. Secondary end point secondary objective: • Bone marrow blast counts by morphology and multi-color flow cytometry (MFCM) after course #1 and #2 and before allo-SCT; ORR (CR, CRp, and CRi) and morphologic leukemia-free state (MLFS) rates after course #1 and #2; MRD negativity after course #1 and #2 and before allo-SCT; absolute MRD levels after course #1 and #2 and before allo-SCT. • OS • DFS • CIR.
2. Secondary end point secondary objective: • Cumulative toxicity, defined as the total of grade ≥3 AEs from the start of AML treatment to the end of the reporting period, which are graded by NCI CTCAE version 5.0. • NRM.
3. Secondary end point induction randomization: • Bone marrow blast counts by morphology and multi-color flow cytometry (MFCM) after course #1 and #2 and before allo-SCT; ORR (CR, CRp, and CRi) and morphologic leukemia-free state (MLFS) rates after course #1 and #2; MRD negativity after course #2 and before allo-SCT; absolute MRD levels after course #1 and #2 and before allo-SCT. OS • DFS • EFS • CIR • OS
4. Secondary end point induction randomization: • Cumulative toxicity, defined as the total of AESIs over time, which are graded by NCI CTCAE version 5.0. • Adverse events (AEs), as characterized by type, frequency, severity (as graded using CTCAE, v5.0). • Serious adverse events (SAEs), as characterized by type, frequency, severity (as graded using CTCAE, v5.0). • NRM.
5. Secondary end point consolidation randomization: • Cumulative toxicity, defined as the as the total of grade ≥3 AEs over time, which are graded by NCI CTCAE version 5.0. • Non-relapse mortality (NRM).
6. Secondary end point consolidation randomization: Cumulative Hospitalized Days
7. Secondary end point consolidation randomization: •OS •CIR
8. Secondary end point secondary objective: Entire study population: to establish a prospective data registry of relapsed and refractory pediatric AML patients to identify risk factors and improve therapeutic strategies for this population.

Investigational products

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

Test 1

Auxiliary 11

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Prinses Maxima Centrum voor Kinderoncologie B.V.

Sponsor organisation

Prinses Maxima Centrum voor Kinderoncologie B.V.

Address

Heidelberglaan 25

City

Utrecht

Postcode

3584 CS

Country

Netherlands

Scientific contact point

Organisation

Prinses Maxima Centrum voor Kinderoncologie B.V.

Contact name

Prof. Dr. Gertjan J.L. Kaspers

Public contact point

Organisation

Prinses Maxima Centrum voor Kinderoncologie B.V.

Contact name

Secretariat TDC

Locations

12 EU/EEA countries · 52 investigational sites

By country

Investigational sites

Country notifications

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

Oversight and notifications

Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77

Serious breaches 1 · Art. 52 CTR

Urgent safety measures 1 · Art. 54 CTR

Results and documents

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

Documents 259 files

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

Application history

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