Clinical Trials Register

Summary
EudraCT Number:	2022-002885-34
Sponsor's Protocol Code Number:	CHIP-AML22/Master
National Competent Authority:	Netherlands - Competent Authority
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2023-01-10
Trial results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Netherlands - Competent Authority

A.2

EudraCT number

2022-002885-34

A.3

Full title of the trial

CHIP-AML22 Master protocol: An open label complex clinical trial in newly diagnosed pediatric de novo AML patients – a study by the NOPHO-DB-SHIP consortium

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

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

A.3.2

Name or abbreviated title of the trial where available

CHIP-AML22/Master

A.4.1

Sponsor's protocol code number

CHIP-AML22/Master

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Princess Máxima Center
B.1.3.4	Country	Netherlands
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	EUROPEAN COMMISSION
B.4.2	Country	Belgium
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Princess Máxima Center
B.5.2	Functional name of contact point	Trial and Data Center
B.5.3	Address:
B.5.3.1	Street Address	Heidelberglaan 25
B.5.3.2	Town/ city	Utrecht
B.5.3.3	Post code	3584 CS
B.5.3.4	Country	Netherlands
B.5.4	Telephone number	+31889727272
B.5.6	E-mail	trialmanagement@prinsesmaximacentrum.nl

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Comparator
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Cytarabine
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.4	Pharmaceutical form	Solution for injection/infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Cytarabine
D.3.9.3	Other descriptive name	Cytarabine
D.3.9.4	EV Substance Code	SUB06880MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	100
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Comparator
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Etoposide
D.3.4	Pharmaceutical form	Concentrate for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Etoposide
D.3.9.3	Other descriptive name	Etoposide
D.3.9.4	EV Substance Code	SUB07337MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	20
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 3
D.1.2 and D.1.3	IMP Role	Comparator
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Methotrexate
D.3.4	Pharmaceutical form	Solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intrathecal use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Methotrexate
D.3.9.3	Other descriptive name	Methotrexate
D.3.9.4	EV Substance Code	SUB08856MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	6 to 12
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Acute Myeloid Leukemia

E.1.1.1

Medical condition in easily understood language

Blood cancer

E.1.1.2

Therapeutic area

Diseases [C] - Cancer [C04]

MedDRA Classification

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

• Overarching objective:
To improve the overall EFS for children and adolescents with newly diagnosed AML, compared to NOPHO-DBH AML-2012.

• 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

E.2.2

Secondary objectives of the trial

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.

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)

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

A phase II, single arm, open label, study on the safety, efficacy, pharmacokinetics and pharmacodynamics of quizartinib in combination with chemotherapy and as single-agent after high dose therapy in newly diagnosed pediatric FLT3-ITD positive and NPM1 wild-type AML patients
(A linked-trial of the CHIP-AML22/Master protocol by the NOPHO-DB-SHIP consortium)
version 1.0, dd-mm-2022
EudraCT number: 2022-002886-14

Primary Objective:
• Efficacy:
To assess the clinical benefit of quizartinib as measured by the MRDnegativity rate (defined as <0.1% using flow-cytometry) after up to two courses of conventional chemotherapy plus quizartinib, in newly diagnosed pediatric de novo AML with a FLT3-ITD and without a concurrent NPM1 mutation.
• Safety:
During the safety run-in, the co-primary objective will be to determine the Recommended Phase 2 Dose (RP2D) of quizartinib for newly diagnosed pediatric AML patients with a FLT3-ITD and without a concurrent NPM1 mutation, based on the safety and tolerability profile of quizartinib observed at dose levels.

Secondary Objectives:
• Efficacy:
To explore the added anti-leukemic effect of quizartinib based on other measures of response, as defined as secondary endpoints, including morphological overall response rate (ORR), MRD by MFCM, event free survival (EFS), overall survival (OS), disease free survival (DFS), duration of response, cumulative incidence of relapse (CIR), number and percentage of patients actually being treated with hematopoietic stem cell transplantation (HSCT), number of patients starting and completing continuation treatment post-HSCT.
• Safety:
To describe the safety and tolerability of combining quizartinib with conventional treatment and quizartinib given as single-agent after HSCT
• Pharmacokinetics (PK) :
To characterize the pharmacokinetics of quizartinib and its main circulating active metabolite AC886
• Palatability of quizartinib formulations:
To assess the palatability of quizartinib formulations.

E.3

Principal inclusion criteria

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.

Additional inclusion criteria for the consolidation randomization
• Stratified to standard-risk group (SR) at the end of induction (EOI)
• Signed informed consent for the consolidation randomization. Standard of care consolidation treatment (HAM) may be started before this informed consent has been obtained.

E.4

Principal exclusion criteria

1) Previous chemotherapy or radiotherapy. This includes patient with therapy-related AML after previous cancer therapy.
2) Patients with a (known) germline predisposition for bone marrow failure, like Fanconi anemia.
3) Myeloid Leukemia of Down syndrome (MLDS).
4) Acute promyelocytic leukemia (APL).
5) Myelodysplastic syndrome (MDS).
6) Juvenile Myelomonocytic Leukemia (JMML).
7) Known intolerance to any of the chemotherapeutic drugs in the protocol.
8) Evidence of cardiac dysfunction (shortening fraction below 28%).
9) Pregnant or lactating patients, or sexually active female patients of childbearing potential not willing to use a highly effective method of contraception for the duration of study therapy and up to 7 months after the completion of all study therapy.
10) Sexually active, fertile male patients must use a condom during intercourse, and agree not to father a child or donate sperm during therapy, for the duration of study therapy, and up to 4 months after the completion of all study therapy.
11) Concomitant administration of any other experimental drug under investigation, 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, is not allowed.
12) Patients who in the opinion of the investigator, may not be able to comply with the study requirements of the study.
13) Patients with known active hepatitis B, hepatitis C, or HIV infection.
14) Patients for whom informed consent was not obtained.

E.5 End points

E.5.1

Primary end point(s)

Event Free Survival (EFS)

E.5.1.1

Timepoint(s) of evaluation of this end point

5 years after diagnosis

E.5.2

Secondary end point(s)

Entire study population:
• 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
• Cumulative toxicity, defined as the total of all grades AEs over time, which are graded by NCI CTCAE version 5.0.
• NRM.

Consolidation randomization:
• Cumulative toxicity, defined as the total of all grades AEs over time, which are graded by NCI CTCAE version 5.0.
• NRM
• Cumulative Hospitalized Days
• OS
• CIR

E.5.2.1

Timepoint(s) of evaluation of this end point

5 years after diagnosis

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

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

E.8.1.4

Double blind

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

• Overall: historical cohort from NOPHO-DBH AML2012 • Consolidation randomization: 2 vs. 3 courses

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

Yes

E.8.4

The trial involves multiple sites in the Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Hong Kong

Israel

Estonia

Finland

Iceland

Latvia

Lithuania

Sweden

Netherlands

Spain

Belgium

Denmark

Norway

Portugal

E.8.7

Trial has a data monitoring committee

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

LVLS

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

Yes

F.1.1

Number of subjects for this age range:

890

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

Yes

F.1.1.3.1

Number of subjects for this age range:

F.1.1.4

Infants and toddlers (28 days-23 months)

Yes

F.1.1.4.1

Number of subjects for this age range:

245

F.1.1.5

Children (2-11years)

Yes

F.1.1.5.1

Number of subjects for this age range:

270

F.1.1.6

Adolescents (12-17 years)

Yes

F.1.1.6.1

Number of subjects for this age range:

355

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

This study will be conducted in patients ≥1 day of age and ≤18 years. For minors the informed consent of the parents or legal guardians will be mandatory.

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

120

F.4.2

For a multinational trial

F.4.2.1

In the EEA

705

F.4.2.2

In the whole clinical trial

905

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

Not other than normal care

G. Investigator Networks to be involved in the Trial
G.4 Investigator Network to be involved in the Trial: 1
G.4.1	Name of Organisation	NOPHO-DB-SHIP

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2023-01-10

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2023-03-17

P. End of Trial
P.	End of Trial Status	Ongoing

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