Clinical Trials Register

Summary
EudraCT Number:	2013-004481-34
Sponsor's Protocol Code Number:	Uni-Koeln-1694
National Competent Authority:	Netherlands - Competent Authority
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2016-02-24
Trial results	View 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

2013-004481-34

A.3

Full title of the trial

RANDOMIZED PHASE 2 TRIAL COMPARING EXPERIMENTAL IMMUNOTHERAPY (ANTI-GD2 ANTIBODY, IL-2 S.C.,GM-CSF) IN RECURRENT HIGH RISK NEUROBLASTOMA PATIENTS WITH STANDARD IMMUNOTHERAPY (ANTI-GD2 ANTIBODY, IL-2 I.V., GM-CSF) IN PATIENTS WITH RECURRENT AND NEWLY DIAGNOSED HIGH RISK NEUROBLASTOMA

A.3.1

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

Immunotherapy for patients with high risk neuroblastoma

A.3.2

Name or abbreviated title of the trial where available

NB2013-HR PILOT GPOH/DCOG

A.4.1

Sponsor's protocol code number

Uni-Koeln-1694

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	University of Cologne
B.1.3.4	Country	Germany
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	United Therapeutics
B.4.2	Country	United States
B.4.1	Name of organisation providing support	Initiative “Leverkusen hilft krebskranken Kindern e.V."
B.4.2	Country	Germany
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Paediatric Oncology and Haematology
B.5.2	Functional name of contact point	Neuroblastomstudie
B.5.3	Address:
B.5.3.1	Street Address	Kerpener Str. 62
B.5.3.2	Town/ city	Cologne
B.5.3.3	Post code	50924
B.5.3.4	Country	Germany
B.5.4	Telephone number	+492214786853
B.5.5	Fax number	+492214786851
B.5.6	E-mail	neuroblastomstudie@uk-koeln.de

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
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	Dinutuximab
D.2.1.1.2	Name of the Marketing Authorisation holder	United therapeutics
D.2.1.2	Country which granted the Marketing Authorisation	United Kingdom
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	Yes
D.2.5.1	Orphan drug designation number	EU/3/11/879
D.3 Description of the IMP
D.3.1	Product name	chimeric monoclonal antibody 14.18
D.3.2	Product code	ch14.18
D.3.4	Pharmaceutical form	Solution for infusion
D.3.4.1	Specific paediatric formulation	Yes
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	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)	Yes
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	Test
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	Leukine
D.2.1.1.2	Name of the Marketing Authorisation holder	Sanofi Aventis
D.2.1.2	Country which granted the Marketing Authorisation	United States
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	Leukine
D.3.4	Pharmaceutical form	Powder for solution for injection/infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use Subcutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	SARGRAMOSTIM
D.3.9.1	CAS number	123774-72-1
D.3.9.4	EV Substance Code	SUB10450MIG
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	250
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	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)	Yes
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	Yes
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	Test
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.2.1.2	Country which granted the Marketing Authorisation	Germany
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	Powder for 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	Aldesleukin
D.3.9.1	CAS number	8000048-25-1
D.3.9.3	Other descriptive name	INTERLEUKIN-2
D.3.9.4	EV Substance Code	SUB14225MIG
D.3.10	Strength
D.3.10.1	Concentration unit	IU/ml international unit(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	18000000
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	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)	Yes
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	Yes
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: 4
D.1.2 and D.1.3	IMP Role	Test
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.2.1.2	Country which granted the Marketing Authorisation	Germany
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	Powder for solution for injection/infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Subcutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Aldesleukin
D.3.9.1	CAS number	8000048-25-1
D.3.9.3	Other descriptive name	INTERLEUKIN-2
D.3.9.4	EV Substance Code	SUB14225MIG
D.3.10	Strength
D.3.10.1	Concentration unit	IU/ml international unit(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	18000000
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	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)	Yes
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	Yes
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

Recurrent, progressive or newly diagnosed high risk neuroblastoma

E.1.1.1

Medical condition in easily understood language

neuroblastoma - childhood cancer

E.1.1.2

Therapeutic area

Diseases [C] - Cancer [C04]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	18.1
E.1.2	Level	PT
E.1.2	Classification code	10029260
E.1.2	Term	Neuroblastoma
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

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

The primary trial objective is the safety and tolerability of the two immunotherapy regimens for patients with recurrent high risk neuroblastoma and of the standard immunotherapy regimen for newly diagnosed high risk neuroblastoma (three arm trial).

E.2.2

Secondary objectives of the trial

Reduction of grade 2-4 key side effects in the experimental arm.

Neuralgia (with assessment of pain duration (days requiring morphin) and maximum grade of pain scores during first 2 antibody cycles)

Comparison of pharmacokinetics of antibody ch14.18 in both arms.

Comparison of immune response between treatment cycles, treatment arms and between recurrent and newly diagnosed patients.

Comparison of grade 2-4 toxicities between intravenously and subcutaneously administered IL-2.

2 year event free (EFS), progression free (PFS), and overall survival rates (OS) from time of randomization.

Tumor response at the end of treatment and time to progression (TTP)

Quality of Life (QoL)

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Established diagnosis of neuroblastoma according to the international INSS criteria

High risk (HR): stage 4 over 18 months of age and MYCN amplified neuroblastoma of any stage and any age
- Recurrent or progressive neuroblastoma: completed re-induction chemotherapy (Germany and The Netherlands)
- Newly diagnosed neuroblastoma: Complete front-line treatment including induction chemotherapy, surgical removal and/ or local irradiation of the primary tumor and myeloablative chemotherapy with autologous stem cell reinfusion according to the actual guidelines of the GPOH/ DCOG (in The Netherlands only).

Achieved response status: stable disease or better (CR, VGPR, PR, SD) at the end of re-induction chemotherapy in recurrent disease and after ASCT in newly diagnosed disease

Written informed consent of parents or guardian and – if appropriate – of the patient.

For at least two weeks prior to start of trial medication
- off any standard or experimental treatment (and fully recovered from short-term major toxic effects)
- no tumour surgery (and fully recovered from any post-surgical complications)
- no immediate requirements for palliative chemotherapy, radiotherapy or surgery

The patient may have had prior CNS metastases provided the following criteria are all met:
- The patient’s CNS disease has been previously treated
- The patient’s CNS disease has been clinically stable for four weeks prior to starting this study (assessed clinically and by MRI or CT)
- The patient is off steroids for four weeks prior to starting the study and will not require them during the course of the study
- A patient with seizure disorders may be enrolled if well controlled on anticonvulsants and if no seizures have occurred within a 6 week period prior to starting trial treatment

HIV sero-negative and neither active nor chronic-replicative hepatitis B infection

adequate functions of the cor, lung, bone marrow, liver, kidney

E.4

Principal exclusion criteria

Significant intercurrent illnesses and/or any of the following:
- Symptoms of congestive heart failure or of uncontrolled cardiac arrhythmia
- Significant psychiatric disabilities or psychological conditions preventing treatment realization
- Uncontrolled seizure disorders
- Active infections
- Clinically significant neurologic deficit or objective peripheral neuropathy (> grade 2)
- Significant, symptomatic pleural effusions

Requirement or likely requirement for corticosteroids or other immunosuppressive drugs (except the medications recommended for conditions mentioned in the protocol)

Platelet transfusion dependency

Concurrent treatment with any non-trial anticancer therapy or interventional study

Positive pregnancy test, lactation

Sexually active patients (male and female) at reproductive age not willing to use highly effective contraceptive methods according to the guidelines ICH M3

Neuroblastoma patients with actively progressing disease

Patients with HACA detected after previous antiGD2 immunotherapy

Known allergy or contraindications against one of the study drugs (IMP)

E.5 End points

E.5.1

Primary end point(s)

Safety (toxic deaths) and tolerability (grade 4 toxicities) for the three treatment arms.

E.5.1.1

Timepoint(s) of evaluation of this end point

continously during treatment

E.5.2

Secondary end point(s)

E.5.2.1

Timepoint(s) of evaluation of this end point

continously resp. at several time-points during treatment (side effects, neuralgia, pharmacokinetics, immune response)

at 2 years (EFS, PFS, OS)

at end of treamtent (tumor response)

at progression (TTP)

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

Yes

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

Yes

E.6.13.1

Other scope of the trial description

Immune response, Quality of life

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)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

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

Yes

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

dose and route of application of interleukine 2

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

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial has a data monitoring committee

Yes

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

Last visit last subject (LVLS), 24 months after inclusion of the last patient

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

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:

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)

F.1.1.4

Infants and toddlers (28 days-23 months)

Yes

F.1.1.4.1

Number of subjects for this age range:

F.1.1.5

Children (2-11years)

Yes

F.1.1.5.1

Number of subjects for this age range:

F.1.1.6

Adolescents (12-17 years)

Yes

F.1.1.6.1

Number of subjects for this age range:

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

children below 18 years

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

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)

After completion of trial treatment, no further treatment is planned. After the minimun follow-up time the patients may participate in another trial or will be followed according to routine clinical care.

G. Investigator Networks to be involved in the Trial

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

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2016-02-24

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2016-10-06

P. End of Trial
P.	End of Trial Status	Prematurely Ended
P.	Date of the global end of the trial	2016-10-28

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