Clinical Trials Register

Summary
EudraCT Number:	2011-003496-11
Sponsor's Protocol Code Number:	EN3348-303
National Competent Authority:	Poland - Office for Medicinal Products
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2011-11-03
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

Poland - Office for Medicinal Products

A.2

EudraCT number

2011-003496-11

A.3

Full title of the trial

A Phase 3, Randomized, Active-Controlled, Open-Label, Multicenter Study to Evaluate the Efficacy and Safety of EN3348 (MCC) as Compared with Mitomycin C in the Intravesical Treatment of Subjects with BCG Recurrent or Refractory Non-Muscle Invasive Bladder Cancer

A.3.1

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

not applicable

A.4.1

Sponsor's protocol code number

EN3348-303

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT01200992

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	Endo Pharmaceuticals Inc.
B.1.3.4	Country	United States
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Endo Pharmaceuticals Inc.
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Endo Pharmaceuticals Inc.
B.5.2	Functional name of contact point	Oncology Therapeutic Area
B.5.3	Address:
B.5.3.1	Street Address	100 Endo Boulevard
B.5.3.2	Town/ city	Chadds Ford, PA
B.5.3.3	Post code	19317
B.5.3.4	Country	United States
B.5.4	Telephone number	+1610459 7556
B.5.5	Fax number	+1484840 4290
B.5.6	E-mail	Lang.zhihui@endo.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.3.2	Product code	EN3348
D.3.4	Pharmaceutical form	Suspension for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravesical use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.9.2	Current sponsor code	EN3348
D.3.9.3	Other descriptive name	MCC, mycobacterial cell wall-DNA complex
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	1.0
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	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	Yes
D.3.11.13.1	Other medicinal product type	EN3348 is a mycobacterial cell wall-DNA complex prepared from a pure culture of Mycobacterium phlei
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.2.1.1.1	Trade name	Mitomycin-C Kyowa
D.2.1.1.2	Name of the Marketing Authorisation holder	Kyowa Hakko Kirin UK Ltd.
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	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Mitomycin C
D.3.4	Pharmaceutical form	Powder for solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravesical use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Mitomycin
D.3.9.1	CAS number	50-07-7
D.3.9.3	Other descriptive name	Mitomycin C
D.3.9.4	EV Substance Code	SUB09006MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	40
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	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

BCG Recurrent or Refractory Non-Muscle Invasive Bladder Cancer

E.1.1.1

Medical condition in easily understood language

Bladder 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	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	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

To evaluate the efficacy of EN3348 as compared with mitomycin C in the treatment of subjects with BCG recurrent or refractory NMIBC.

E.2.2

Secondary objectives of the trial

To evaluate the safety of EN3348 as compared with mitomycin C in the treatment of subjects with BCG recurrent or refractory NMIBC.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Males and females who are 18 years of age or older at time of consent signing
2. Have either BCG recurrent or refractory NMIBC:
a. Refractory disease is defined as evidence of persistent high grade bladder cancer (TaHG, T1, and/or CIS) at least 6 months from the start of a full induction course of BCG with or without maintenance/re-treatment at 3 months
b. Recurrent disease is defined as reappearance of disease after achieving a tumor-free status by 6 months following a full induction course of BCG with or without maintenance/re-treatment at 3 months. Subjects with recurrent disease must have recurred within 18 months following the last dose of BCG
3. Have histologically confirmed NMIBC (according to 2004 WHO classification) within 8 weeks prior to randomization:
a. High grade Ta papillary lesion(s)
b. High or low grade T1 papillary lesion(s) (biopsy sample must include evidence of muscularis propria)
c. CIS, with or without Ta or T1 papillary tumor(s) of any grade
4. Have had all visible papillary lesion(s) resected by TURBT within 8 weeks prior to randomization
5. Available for the duration of the study including follow-up (approximately 36 months)
6. Have an Eastern Cooperative Oncology Group (ECOG) performance status grade of 2 or less
7. Have no evidence of urothelial carcinoma involving the upper urinary tract or urethra (confirmed by extravesical work up, which may include radiological imaging and/or biopsy) within 6 months of randomization:
a. If previous work up occurred more than 6 months prior randomization, extravesical work up must be repeated prior to randomization in order to determine eligibility
8. Subjects (male and female) of child-bearing potential (including female subjects who are post-menopausal for less than 1 year) must be willing to practice effective contraception (as defined by the Investigator) while on treatment and be willing and able to continue contraception for 30 days after their last dose of study treatment.
9. Is able to understand and give written informed consent

E.4

Principal exclusion criteria

1. Current or previous history of muscle invasive bladder tumors
2. Current or previous history of positive lymph nodes and/or metastatic bladder cancer
3. Current evidence of pure squamous cell carcinoma, pure adenocarcinoma or pure undifferentiated carcinoma of the bladder
4. Currently receiving systemic cancer therapy (cytotoxic/cytostatic or immunotherapy)
5. Currently receiving treatment with a prohibited therapy
6. Current or prior history of systemic lupus erythematosus
7. Systemic immunotherapy within 6 months of randomization
8. Treatment with an investigational agent within 30 days or 5 half lives from randomization, whichever is longer
9. Prior treatment with an intravesical chemotherapeutic agent within 3 months of randomization, with the exception of a single perioperative dose of chemotherapy immediately post-TURBT (not considered treatment)
10. Prior treatment with EN3348 (MCC) or any other mycobacterial cell wall composition or formulation
11. Refractory to mitomycin C (failure to achieve tumor-free status following minimum of a 6-week induction course of mitomycin C) at any time in the subject’s disease history
12. Contraindication to mitomycin C
13. Untreated urinary tract or bladder infection
14. ANC <1000/μL and hemoglobin <10 g/dL
15. Known cardiovascular disease such as myocardial infarction within the past 3 months, unstable angina pectoris, congestive heart failure (New York Heart Association [NYHA] Class III or IV) or uncontrolled cardiac arrhythmia
16. Female subjects who are pregnant or lactating
17. Congenital or acquired immune deficiency
18. Have current or history of documented or suspected malignancy of any organ system (diagnosed, treated or untreated) within the past 5 years (with the exception of localized transitional cell carcinoma of the ureter treated with ureterectomy or nephroureterectomy, adequately treated basal cell or squamous cell carcinoma of the skin or asymptomatic non-metastatic prostate cancer either previously successfully treated or currently under active surveillance or receiving hormone therapy only)
19. Bladder contracture or history of an inability to retain the instillate for a minimum of 1 hour, even with premedication
20. Inability to tolerate intravesical administration or intravesical surgical manipulation (cystoscopy or biopsy)
21. Clinically significant active infections
22. Any medical or psychiatric condition which, in the opinion of the investigator, would preclude the participant from adhering to the protocol or completing the trial per protocol

E.5 End points

E.5.1

Primary end point(s)

Event-free survival - the interval from randomization to an event

E.5.1.1

Timepoint(s) of evaluation of this end point

Depends on the response of the subject to the treatment. Please refer to section 11.1 of the Protocol

E.5.2

Secondary end point(s)

• Event-free survival rate at 1 and 2 years
• Recurrence rate at 1 and 2 years
• Progression rate at 1 and 2 years – number of subjects progressing to muscle invasive disease (T2 or higher) or metastatic bladder cancer observed outside of bladder
• Time to cystectomy – interval from randomization to cystectomy
• Overall survival

E.5.2.1

Timepoint(s) of evaluation of this end point

• Event-free survival rate, Recurrence rate, Progression rate - at 1 and 2 years
• Time to cystectomy – interval from randomization to cystectomy

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

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)

Yes

E.8.2.2

Placebo

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

Canada

India

United States

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

Defined as 12 months after the last subject is randomized or 282 events have occurred, whichever occurs later or the Sponsor terminates the study

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:

180

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

270

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

F.4.2.2

In the whole clinical trial

450

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)

Standard of 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

2012-02-08

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2012-01-12

P. End of Trial
P.	End of Trial Status	Prematurely Ended
P.	Date of the global end of the trial	2013-03-06

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