Clinical Trials Register

Summary
EudraCT Number:	2009-018077-31
Sponsor's Protocol Code Number:	012010
National Competent Authority:	Ireland - HPRA
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2012-10-11
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

Ireland - HPRA

A.2

EudraCT number

2009-018077-31

A.3

Full title of the trial

A PHASE I/II DOSE SCHEDULE FINDING STUDY
FOR CH14.18/CHO CONTINUOUS INFUSION COMBINED WITH SUBCUTANEOUS ALDESLEUKIN (IL-2)
IN PATIENTS WITH PRIMARY REFRACTORY OR RELAPSING NEUROBLASTOMA

A.3.1

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

Long term continuous infusion ch14.18/CHO plus s.c. aldesleukin (IL-2) randomised

A.3.2

Name or abbreviated title of the trial where available

Long term continuous infusion ch14.18/CHO

A.4.1

Sponsor's protocol code number

012010

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	St. Anna Kinderkrebsforschung/CCRI
B.1.3.4	Country	Austria
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	FWF-KLIF
B.4.2	Country	Austria
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Children's Cancer Research Institute
B.5.2	Functional name of contact point	Ruth Ladenstein
B.5.3	Address:
B.5.3.1	Street Address	Zimmermannplatz 10
B.5.3.2	Town/ city	Wien
B.5.3.3	Post code	1090
B.5.3.4	Country	Austria
B.5.4	Telephone number	+431404704775
B.5.5	Fax number	+431404707430
B.5.6	E-mail	ruth.ladenstein@stanna.at

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	No
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	ch14.18/CHO
D.3.2	Product code	ch14.18/CHO
D.3.4	Pharmaceutical form	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	ch14.18/CHO
D.3.9.3	Other descriptive name	ch14.18/CHO
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	4.6
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: 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	Proleukin
D.2.1.1.2	Name of the Marketing Authorisation holder	Novartis Pharma
D.2.1.2	Country which granted the Marketing Authorisation	Austria
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	Aldesleukin
D.3.4	Pharmaceutical form	Powder and solvent for solution for injection
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	interleukin-2
D.3.9.1	CAS number	110942-02-4
D.3.9.2	Current sponsor code	PL 00101/0936
D.3.9.3	Other descriptive name	ALDESLEUKIN
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: 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.2.1.1.1	Trade name	Isotretinoin
D.2.1.1.2	Name of the Marketing Authorisation holder	ratiopharm Arzneimittel, Wien
D.2.1.2	Country which granted the Marketing Authorisation	Austria
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	Isotretinoin
D.3.4	Pharmaceutical form	Capsule, soft
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	ISOTRETINOIN
D.3.9.1	CAS number	7429-90-5D
D.3.9.3	Other descriptive name	Roaccutan
D.3.9.4	EV Substance Code	SUB08341MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg/m2 milligram(s)/square meter
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	160
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

High-risk neuroblastoma patients having received at least one previous high dose treatment followed by stem cell rescue after conventional therapy fulfilling one of the following criteria:
• Primary refractory patients with stage 4 disease with at least two lines of treatment prior to HDT/SCT, causing a delay from diagnosis to SCT of over 9 months
• Relapse after primary stage 4 disease
• Disseminated relapse after primary localized neuroblastoma

E.1.1.1

Medical condition in easily understood language

Neuroblastoma

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

To find an improved treatment schedule which reduces the pain-toxicity profile of ch14.18/CHO whilst maintaining immunomodulatory efficacy in patients (1-21 years old) with primary refractory (≥ 2 lines of conventional treatment) or relapsed neuroblastoma through prolonged continuous infusion in combination with s.c aldesleukin (IL-2).
V3: Based on the IL-2 toxicity profile and recent data from the HRNBL1 SIOPEN trial, the study committee decided to evaluate the role of IL-2 for EFS (event free survival) in the LTI setting by randomizing the current standard arm against an ch14.18/CHO only treatment arm (additional randomised question = ARAQ). The use of isotretinoin remains unchanged in both treatment arms

E.2.2

Secondary objectives of the trial

To assess pain intensity and relief by appropriate medication with a validated self- report tool.
To validate, during the first course, the correlation between activated NK cells and ch14.18/CHO level with ADCC by using MNC and serum from patients on day 15.
To determine systemic immune modulation/response resulting from the combined treatment of ch14.18/CHO and s.c. aldesleukin (IL-2) by repeated analysis of NK-cell activation, soluble IL-2 receptor, ADCC, CDC and anti-idiotype activation (HAMA and HACA).
To achieve an increase in absolute lymphocyte counts and absolute NK cell numbers after the respective cycles as a measurement of response to s.c. aldesleukin (IL-2).
To determine the pharmacokinetics of ch14.18/CHO.
To evaluate anti-tumour responses resulting from this treatment regimen through clinical assessments in patients with measurable disease.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Key inclusion criteria
Patients with neuroblastoma >1 and ≤ 21 years of age (age limit for trial cohorts only), having received at least one previous high dose treatment followed by stem cell rescue after conventional therapy to reduce tumour burden fulfilling one of the following criteria:
• Primary refractory patients with stage 4 disease with at least two lines of treatment prior to HDT/ASCT, causing a delay from diagnosis to ASCT of over 9 months. (For example, patients who are on the current high-risk SIOPEN trial (HR-NBL-1/SIOPEN) and have completed high-dose treatment but are ineligible for the R2 randomization due to major delays for toxicity).
• Relapse after primary stage 4 disease.
• Disseminated relapsed neuroblastoma having received ASCT.
Patients must have a life expectancy of at least 12 weeks.

Patients who received previus treatments with ch14.18 SP2/0 or ch14.18/CHO are eligible if they test negative for human anti-chimeric antibodies (HACA) at screening.

Patients who are platelet transfusion dependent are eligible if they adequately respond to platelet transfusion (>20.000/µl)

Patients who take topical and local acting immunosuppressive drugs without relevant systemic activity such as cremes, inhalative and immunosuppressive drugs acting on mucoasal membranes are allowed on the trial.

A substitute test for patients who can not perform a pulmonary function test was defined in order to assess pulmonary function prior to immunotherapy: Pulse oximetry at room air. Patients with a reading ≥ 94% are eligible.

E.4

Principal exclusion criteria

Progressive disease and previous treatment with ch14.18/SP2/0 and/or ch14.18/CHO

E.5 End points

E.5.1

Primary end point(s)

The primary endpoint is event free survival calculated from the date of randomisation. The following will be considered as events:
- disease progression or relapse,
- death from any cause
- second neoplasm

E.5.1.1

Timepoint(s) of evaluation of this end point

The final analysis will be performed 1 year after the closure of the randomisation. All analyses will be intention to treat, i.e. with all patients analysed in the arm to which they were randomised

E.5.2

Secondary end point(s)

Biomarkers
Response criteria
Immunological assessments

E.5.2.1

Timepoint(s) of evaluation of this end point

Descriptive analysis of serum biomarkers at different time points during treatment will be performed.
Response analysis - All patients who complete the first cycle will be considered evaluable for anti-tumour response.

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

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

Yes

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)

Yes

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

Yes

E.7.1.3.1

Other trial type description

dose finding study

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

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)

Information not present in EudraCT

E.8.2.2

Placebo

Information not present in EudraCT

E.8.2.3

Other

Information not present in EudraCT

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in 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

Australia

Austria

France

Germany

Hong Kong

Israel

Italy

Spain

United Kingdom

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

The end of trial is defined as the date of the last visit of the last patient undergoing the trial. This will allow sufficient time for the completion of protocol procedures, data collection and data input.

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:

444

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:

200

F.1.1.5

Children (2-11years)

Yes

F.1.1.5.1

Number of subjects for this age range:

120

F.1.1.6

Adolescents (12-17 years)

Yes

F.1.1.6.1

Number of subjects for this age range:

114

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.1.3.1

Number of subjects for this age range:

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

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

430

F.4.2.2

In the whole clinical trial

444

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)

None

G. Investigator Networks to be involved in the Trial
G.4 Investigator Network to be involved in the Trial: 1

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

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2012-12-07

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2012-11-20

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

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