Clinical Trials Register

Summary
EudraCT Number:	2009-015936-14
Sponsor's Protocol Code Number:	CH14.181021
National Competent Authority:	Austria - BASG
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2010-02-02
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

Austria - BASG

A.2

EudraCT number

2009-015936-14

A.3

Full title of the trial

PHASE II FEASIBILITY STUDY USING CH14.18/CHO ANTIBODY AND SUBCUTANEOUS INTERLEUKIN 2 AFTER HAPLOIDENTICAL STEM CELL TRANSPLANTATION IN CHILDREN WITH RELAPSED NEUROBLASTOMA

A.3.1

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

Study investigating the feasibility of using an antibody (ch14.18/CHO) directed against neuroblastoma and the cyctokine IL2 in the treatment of relapsed neuroblastoma patients after haploidentical stem cell transplantation

A.3.2

Name or abbreviated title of the trial where available

CH14.18-IL2 1021

A.4.1

Sponsor's protocol code number

CH14.181021

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 Children´s Hospital Tübingen,
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	Universitätsklinikum Tübingen
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	Universitätsklinikum Tübingen
B.5.2	Functional name of contact point	Peter Lang
B.5.3	Address:
B.5.3.1	Street Address	Geissweg 3
B.5.3.2	Town/ city	Tübingen
B.5.3.3	Post code	72076
B.5.3.4	Country	Germany
B.5.4	Telephone number	497071290

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	recombinant chimeric monoclonal antibody ch14.18
D.3.2	Product code	ch14.18
D.3.4	Pharmaceutical form	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	not applicable
D.3.9.3	Other descriptive name	chimeric monoclonal antibody 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
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)	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	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	Yes
D.3.11.13.1	Other medicinal product type	GD2 specific antibody

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

Pediatric patients with relapsed neuroblastoma

E.1.1.1

Medical condition in easily understood language

Pediatric patients diagnosed and treated for neuroblastoma who had a relapse and received an allogenic haploidentical stem cell transplantation

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	19.1
E.1.2	Level	PT
E.1.2	Classification code	10066595
E.1.2	Term	Neuroblastoma recurrent
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

• Evaluation of safety and feasibility of the chimeric 14.18 anti-GD2 monoclonal antibody (ch14.18/CHO) in combination with subcutaneous aldesleukin (IL-2, (Proleukin®)

E.2.2

Secondary objectives of the trial

• To evaluate the anti-tumour responses resulting from this immunotherapy regimen through clinical assessments (radiographic and clinical measurements, including bone marrow immunohistochemistry for those research participants with marrow involvement).
• To evaluate pharmacokinetics of the ch14.18/CHO.
• To evaluate changes in NK cell activation and proliferation (immunological monitoring).

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

• Less than or equal to 21 years of age.
• Histologically confirmed neuroblastoma.
• Refractory to standard treatment (i.e. refractory disease) or relapse after previous autologous or allogenic stem cell transplantation.
• Patient has undergone haploidentical stem cell transplantation prior to antibody infusion according to appendix IV at least 60 days prior to starting immunotherapy.
• Serum glutamate pyruvate transaminase (SGPT) less than 2.5 times the upper limit of normal for age and total bilirubin less than 2 times the upper limit of normal for age. D-Dimers less than 2 times the upper limit of normal.
• Creatinine clearance or radioisotope GFR greater than or equal to 40 ml/min/1.73m2.
• Cardiac shortening fraction greater than or equal to 20% by echocardiogram.
• Karnofsky/Lansky performance score (age appropriate) of greater than or equal to 50.
• Females of childbearing potential must have a negative pregnancy test. Patients of childbearing potential must agree to use an effective birth control method. Female patients who are lactating must agree to stop breast-feeding.
• Written informed consent is obtained, and for minors a written agreement by parents or legal guardian.
• All institutional and national requirements for human studies are met.

E.4

Principal exclusion criteria

• Marked baseline prolongation of QT/QTc interval (e.g. demonstration of a QTc interval > 450 milliseconds).
• Patients with symptoms of congestive heart failure or uncontrolled cardiac rhythm disturbance.
• Patients with significant psychiatric disabilities or uncontrolled seizure disorders.
• Patients with active infections or active peptic ulcer, unless these conditions are corrected or controlled.
• Patients with acute GvHD Grade III or IV or extensive chronic GvHD.
• Patients with clinically significant, symptomatic, pleural effusions.
• Patients who have had major surgery, (i.e. laparotomy or thoracotomy) within the past two weeks.
• Patients who will more than 12 months post haploidentical stem cell transplantation at the time of starting the first cycle of immunotherapy.
• Prior administration of ch14.18 antibody.
• HIV or Hepatitis B Surface (HBS) Ag positive. As presence of either may influence the ability if the immune system to be stimulated by this treatment.

E.5 End points

E.5.1

Primary end point(s)

Primary endpoint is "success of treatment" defined as a patient receiving the full protocol treatment, still alive 180 days after end of treatment without progression and without unacceptable toxicity and acute GvHD  Grade III or extensive chronic GvHD.
Thus, a composite variable is used as primary endpoint: Treatment success, is defined as a patients who did not experience
1. unacceptable toxicities
2. acute GvHD ≥ Grade III or extensive chronic GvHD
3. other toxicities that did not recover to  Grade 1 within 4 weeks or
4. progressive disease after 6 cycles or
5. deaths within treatment after SCT
6. withdrawal due to other reasons

E.5.1.1

Timepoint(s) of evaluation of this end point

180 days after the end of treatment

E.5.2

Secondary end point(s)

rate and type of dose limiting toxicity, Incidence of GvHD, Progression during treatment, Immunological assessment (cytokine levels, NK activity, immunoreconstitution), Event Free Survival, Overall Survival

E.5.2.1

Timepoint(s) of evaluation of this end point

three years

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

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

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

Yes

E.7.1.3.1

Other trial type description

open phase II trial

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

E.8.1.1

Randomised

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

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

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

The study ends until the patient population of 60 will be reached. All patients will be clinically monitored on a regular medical after care basis also after the study.
The study will be stopped in advance , if unexpected, live threatening (grade 4) side effects or severe acute GvHD (Grade III-IV) occurs in >= 5 out of the first 9 patients, despite dose reductions.

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:

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)

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

F.3.3.1

Women of childbearing potential not using contraception