Clinical Trials Register

Summary
EudraCT Number:	2010-024355-85
Sponsor's Protocol Code Number:	EAURF2010-01
National Competent Authority:	Czechia - SUKL
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2012-03-19
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

Czechia - SUKL

A.2

EudraCT number

2010-024355-85

A.3

Full title of the trial

A randomized, double blind, placebo controlled phase II trial to evaluate the safety and efficacy of recMAGE-A3 + AS15 ASCI in patients with MAGE-A3 positive muscle invasive bladder cancer after cystectomy

A.3.1

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

Safety and Efficacy study of recMAGE-A3 injection in patients with MAGE-A3 positive muscle invasive bladder cancer after cystectomy.

A.3.2

Name or abbreviated title of the trial where available

MAGNOLIA

A.4.1

Sponsor's protocol code number

EAURF2010-01

A.5.4

Other Identifiers

Name:

NTR number

Number:

NTR2846

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	EAU Research Foundation
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	GlaxoSmithKline Biologicals
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	EAU RF
B.5.2	Functional name of contact point	Project Manager
B.5.3	Address:
B.5.3.1	Street Address	Mr. E.N. van Kleffenstraat 5
B.5.3.2	Town/ city	Arnhem
B.5.3.3	Post code	6842 AA
B.5.3.4	Country	Netherlands
B.5.4	Telephone number	+31263890677
B.5.5	Fax number	+31263890679
B.5.6	E-mail	r.schipper@curatrial.com

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	recMAGE-A3 recombinant protein formulated in AS15 adjuvant
D.3.2	Product code	recMAGE-A3 + AS15
D.3.4	Pharmaceutical form	Powder and solvent for suspension for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intramuscular use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.9.1	CAS number	949885-73-8
D.3.9.2	Current sponsor code	recMAGE-A3
D.3.9.3	Other descriptive name	recMAGE-A3 recombinant protein
D.3.10	Strength
D.3.10.1	Concentration unit	µg microgram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	300
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
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Powder and solvent for suspension for injection
D.8.4	Route of administration of the placebo	Intramuscular use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Patients who get a cystectomy due to muscle invasive bladder cancer which is MAGE-A3 positive

E.1.1.1

Medical condition in easily understood language

Patients with a surgically removed urinary bladder due to muscle invasive bladder cancer from which the bladder tumor is MAGE-A3 positive

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	14.1
E.1.2	Level	LLT
E.1.2	Classification code	10022877
E.1.2	Term	Invasive bladder cancer
E.1.2	System Organ Class	100000004864

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

The primary objective of this Phase II study is to evaluate the clinical efficacy in terms of Disease Free Survival of recMAGE-A3 + AS 15 ASCI versus placebo in the overall population patients with bladder cancer with MAGE-A3 expression after cystectomy.

E.2.2

Secondary objectives of the trial

• To evaluate overall survival in the overall study population
• To evaluate Disease-free specific survival (DFSS) in the overall study population
• To evaluate Distant metastasis-free survival (DMFS) in the overall study population
• To evaluate the safety of recMAGE-A3 + AS15 ASCI in the overall study population.
• To evaluate the immune response to recMAGE-A3 + AS15 ASCI in the overall study population.
• Translational research

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Aged greater than or equal to 18 years at the time ICF is signed, either sex.
2. Histologically confirmed (after cystectomy) transitional cell carcinoma of bladder urothelium which is MAGE-A3 positive.
3. Written informed consent for tissue sampling, the mandatory analyses and for the complete study has been obtained prior to the performance of any other protocol-specific procedure.
4. TNM classification at pathological examination of surgically removed specimen: Stage T2,3 N0 or N1 or N2 and M0 disease or Stage T4 N0 M0 disease.
5. The patient is free of residual disease and free of metastasis, as confirmed by a negative baseline Computer Tomogram (CT scan) or Magnetic Resonance Imaging (MRI) of the pelvis, abdomen and chest no more than 9 weeks prior to randomization. Other examinations should be performed as clinically indicated.
6. Patient is fully recovered from surgery within 9 weeks following cystectomy.
7. The patient must have adequate bone-marrow reserve, defined as an absolute neutrophil count ≥ 1.0 x 109/L, and a platelet count ≥ 75 x 109/L, adequate renal function, defined as a serum creatinine ≤ 1.5 times the Upper Limit of Normal (ULN), and adequate hepatic function, defined as a Total bilirubin ≤ 1.5 times the ULN, and a Alanine transaminase (ALAT) and Aspartate Transaminase (ASAT) ≤ 2.5 times the ULN as assessed by standard laboratory criteria.
8. World Health Organization (WHO) performance status 0 – 1 at the time of randomization.
9. If the patient is female, she must be of non-childbearing potential, i.e. have a current tubal ligation, hysterectomy, ovariectomy or be post menopausal, or if she is of childbearing potential, she must practice adequate contraception for 30 days prior to administration of study treatment, have a negative pregnancy test and continue such precautions during all study treatment period and for 2 months after completion of the injection series.
10. The patient should be affiliated to health insurance or benefit of such an insurance

E.4

Principal exclusion criteria

1. The patient has previous or concomitant malignancies at other sites except effectively treated non-melanoma skin cancer, cervical carcinoma in situ, incidental localised prostatic carcinoma or effectively treated malignancy that has been in remission for over 5 years.
2. The patient has received any anti cancer systemic treatment, including immunotherapy(local intravesical BCG is allowed), chemotherapy, or neo-adjuvant chemotherapy, except:
* For the treatment of previous malignancies as allowed by the protocol (i.e., nonmelanoma skin cancer, cervical carcinoma in situ, incidental localised prostatic carcinoma or effectively treated malignancy that has been in remission for over 5 years).
3. The patient has received radiotherapy of the abdominal or pelvic region, within 6 months prior to randomization.
4. Women who are pregnant or breast feeding.
5. The patient has a known infection with human immunodeficiency virus (HIV) or chronic hepatitis B or C.
6. The patient has a history of allergic disease or reactions likely to be exacerbated by any component of the study investigational product.
7. The patient has any confirmed or suspected immunosuppressive or immunodeficient condition or potential immune-mediated diseases. Patients with vitiligo are not excluded to participate in the trial.
8. Patient has received a major organ allograft.
9. The patient requires concomitant treatment with systemic corticosteroids, or any other immunosuppressive agents. Note: the use of prednisone, or equivalent, < 0,125 mg/kg/day (absolute maximum 10 mg/day), or inhaled corticosteroids or topical steroids is permitted.
10. The patient has received any investigational or non-registered medicinal product other than the study medication within the 30 days preceding the first dose of study medication, or plans to receive such a drug during the study.
11. The patient has psychiatric or addictive disorders that may compromise his/her ability to give informed consent or to comply with the trial procedures.
12. The patient has other concurrent severe medical problems, unrelated to the malignancy, that would significantly limit full compliance with the study or expose the patient to unacceptable risk. For example, but not limited to: uncontrolled congestive heart failure or uncontrolled hypertension, unstable heart disease (coronary heart disease or myocardial infarction), uncontrolled arrhythmia or patients taking anticoagulant treatment or having a coagulation disorder.
13. The patient uses alternative treatments eg. plant extracts.
14. Adults under legal supervision

E.5 End points

E.5.1

Primary end point(s)

Disease-free Survival (DFS):
• Defined as the time from randomization to either the date of first recurrence of the disease or the date of death (whatever the cause), whichever occurs first.
• Types of recurrence to be considered as an event include loco-regional and distant
metastases.
• In addition, any death occurring without prior documentation of tumor recurrence will be considered as an event (and will not be censored in the statistical analysis) as this approach is less prone to introduce bias.
• If no event has occurred by the time of the analysis, then the time to event will be censored at the date of the last assessment of the patient in question.
• Any new primary cancer at another site, including transitional carcinoma of the upper urinary tract, will not be considered as recurrence and should be reported as a SAE.

E.5.1.1

Timepoint(s) of evaluation of this end point

Timepoint after randomization at which either the date of first recurrence of the disease or the date of death (whatever the cause), whichever occurs first up to a maximum of 5 years from the first administration of study treatment

E.5.2

Secondary end point(s)

- Overall Survival.
· Defined as the interval from randomization to the date of death, irrespective of the cause of
death; patients still alive will be censored at the date of the last assessment.
- Disease-free specific survival (DFSS).
· Defined as the interval from randomization to the date of first recurrence of disease or date
of death due to bladder carcinoma, whichever occurs first. Patients without recurrence or
death are censored at the date of last assessment. Patients without recurrence who die from another cause are censored at the date of death.
- Distant metastasis-free survival (DMFS).
· Defined as the interval from randomization to the date of first distant metastasis or date of
death, whichever occurs first. Patients alive and without distant metastasis are censored at
the date of last assessment.
- Adverse events.
· Occurrence of adverse events, including potential immune-mediated diseases
- Serious adverse events.
· Occurrence of serious adverse events
- To evaluate the efficacy of the recMAGE-A3 + AS15 ASCI compared to placebo in terms of DFS separately in the population presenting the predictive gene signature, and in the population of patients who do not present this signature
- To evaluate the efficacy of the recMAGE-A3 + AS15 ASCI compared to placebo in terms of
overall survival in the overall study population, in the population of patients presenting the
predictive gene signature and in the population of patients who do not present this signature;
-To evaluate the safety in the overall study population;
- To evaluate the immune response to the recMAGE-A3 + AS15 ASCI in the overall study
population, in the population of patients presenting the predictive gene signature and in the population of patients who do not present this signature
- To evaluate Gene expression profiles of the primary tumor by microarray.

E.5.2.1

Timepoint(s) of evaluation of this end point

Timepoint after randomization at which either the date of first recurrence of the disease or metastase, occurrence of (S)AEs or the date of death (whatever the cause), whichever occurs first up to a maximum of 5 years from the first administration of study treatment

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

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)

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

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

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

Yes

E.8.2.3

Other

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

Ukraine

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 of the last subject

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

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)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

273

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

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

273

F.4.2.2

In the whole clinical trial

273

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)

At the end of the study the clinician will have the prerogative to treat the subject as they would in normal clinical practice.

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

2012-06-27

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2012-03-02

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2016-12-09

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