Clinical Trials Register

Summary
EudraCT Number:	2014-005396-82
Sponsor's Protocol Code Number:	L00070IN312P1
National Competent Authority:	Czechia - SUKL
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2015-12-10
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

2014-005396-82

A.3

Full title of the trial

Randomized phase III study comparing vinflunine-gemcitabine and gemcitabine-carboplatin combinations in patients ineligible to cisplatin with advanced or metastatic urothelial carcinoma.

Randomizované klinické hodnocení fáze III porovnávající kombinace venflunin-gemcitabin a gemictabin-karboplatina u pacientů, kteří nejsou vhodní pro léčbu cisplatinou s pokročilým nebo metastazujícím uroteliálním karcinomem

A.3.1

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

Phase III study comparing vinflunine-gemcitabine and gemcitabine-carboplatin combinations in patients ineligible to cisplatin with advanced or metastatic bladder cancer.

A.3.2

Name or abbreviated title of the trial where available

Jasint-2

A.4.1

Sponsor's protocol code number

L00070IN312P1

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	PIERRE FABRE MEDICAMENT
B.1.3.4	Country	France
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	PIERRE FABRE MEDICAMENT
B.4.2	Country	France
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Pierre Fabre Medicament
B.5.2	Functional name of contact point	Christel LUCAS
B.5.3	Address:
B.5.3.1	Street Address	45 place Abel Gance
B.5.3.2	Town/ city	Boulogne Billancourt
B.5.3.3	Post code	92100
B.5.3.4	Country	France
B.5.4	Telephone number	33(0)1.49.10.83.72
B.5.5	Fax number	33(0)1.49.10.83.28
B.5.6	E-mail	christel.lucas@pierre-fabre.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	Yes
D.2.1.1.1	Trade name	Javlor®
D.2.1.1.2	Name of the Marketing Authorisation holder	Pierre Fabre Médicament
D.2.1.2	Country which granted the Marketing Authorisation	European Union
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	Javlor
D.3.2	Product code	L0070
D.3.4	Pharmaceutical form	Concentrate for 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	VINFLUNINE
D.3.9.1	CAS number	162652-95-1
D.3.9.4	EV Substance Code	SUB00063MIG
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	25
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.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	Gemcitabin Hexal 40mg/ml
D.2.1.1.2	Name of the Marketing Authorisation holder	Hexal AG
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.3.1	Product name	Gemcitabine
D.3.4	Pharmaceutical form	Concentrate for 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	GEMCITABINE
D.3.9.1	CAS number	95058-81-4
D.3.9.4	EV Substance Code	SUB07892MIG
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	200
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.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	Carboplatin Actavis 10mg/ml concentrate for solution for infusion
D.2.1.1.2	Name of the Marketing Authorisation holder	Actavis Group PTC
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.3.1	Product name	carboplatin
D.3.4	Pharmaceutical form	Concentrate for 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	CARBOPLATIN
D.3.9.1	CAS number	41575-94-4
D.3.9.4	EV Substance Code	SUB06614MIG
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	10
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

The trial concerns patients suffering from advanced or metastatic Transitional Cell Carcinoma of the Urothelium (TCCU) who are unfit for Cisplatin-containing first-line treatment due to reduced renal function (GFR 30-60 mL/min)

E.1.1.1

Medical condition in easily understood language

patients suffering from Bladder cancer with reduced renal function

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	LLT
E.1.2	Classification code	10046722
E.1.2	Term	Urothelial carcinoma bladder stage IV
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

To compare the median Progression Free Survival without related Severe Acute Toxicity* between arms (called SAT-PFS).
*[enlarged definition of the Severe Acute Toxicity (SAT) from the EORTC study 30986 adding vinflunine specific risks: neutropenia G4 > 7 days, neutropenic fever G3/4, neutropenic systemic sepsis G3/G4 (neutropenia G3/4), G3/G4 thrombocytopenia with bleeding, G3/4 renal toxicity, G3/4 mucositis, constipation G4 requiring surgery, and death].

E.2.2

Secondary objectives of the trial

- To evaluate the Disease Control Rate (DCR) and the Objective Response Rate (ORR),
- To estimate the Duration of Response of Disease Control and of Stable Disease,
- To estimate the Progression-Free Survival (PFS), Time To Treatment Failure (TTF),
- To estimate the Overall Survival (OS).
- To assess the Tolerance.
- To assess the Quality of Life.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

- Histologically confirmed diagnosis of locally advanced or metastatic predominantly transitional cell carcinoma of the urothelium (TCC) [urinary bladder, kidney, renal pelvis, or ureter],
- Man or woman aged ³ 18 years and < 80 years,
- Signed written informed consent before completing any study-related procedure,
- Ineligibility for cisplatin-based therapy because of renal impaired function (calculated creatinine clearance by Cockroft-Gault formula < 60 mL/min),
- Presence of a “measurable” disease which has not been previously irradiated with at least one uni-dimensional lesion according to RECIST guideline (version 1.1),
- ECOG performance status of 0 or 1 and estimated life expectancy more than 12 weeks
- Patient without prior systemic anticancer therapy for TCC unless cytotoxic agents have been administered in the peri-operative setting (neoadjuvant or adjuvant chemotherapy) and if documented relapse is ³ 6 months after the last dose of chemotherapy,
- Adequate bone marrow and hepatic functions as evidenced by:
o Absolute Neutrophil Count ³ 2.0 x 109/L, Platelet count ³ 100 x 109/L, Haemoglobin ³ 10.0 g/dL
o Serum total bilirubin £ 1.5 x upper limit of normal (ULN), Transaminases £ 2.5x ULN [£ 5 x ULN only in case of liver metastasis]
- Absence of psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; these conditions should be assessed with the patient before randomization in the trial,
- Women of childbearing potential must be using a medically accepted method of contraception to avoid pregnancy during the 2 months preceding the start of study treatment, throughout the study period and for up to 6 months after the last dose of study treatment; women of childbearing potential must have a negative serum or urine pregnancy test within 72 hours prior to the start of study treatment,
- Fertile men must be using an effective method of birth control during the study and up to 6 months after the last dose of study treatment if their partners are women of childbearing potential,
- Patient access to social insurance if applicable in the local regulation.

E.4

Principal exclusion criteria

- ECOG performance status ³ 2,
- Calculated creatinine clearance < 30 mL/min (Cockcroft-Gault formula),
- Known brain metastasis or leptomeningeal involvement (computed tomography scans
not required to rule this out unless there is clinical suspicion of central nervous system
disease),
- Peripheral neuropathy Grade ≥ 2 by National Cancer Institute Common Toxicity Criteria
[NCI CTC],
- Prior radiation to ≥ 30% of the bone marrow or completed < 30 days ago or without full
recovery of toxicities,
- Other serious concomitant/uncontrolled medical condition including:
o Infection requiring systemic anti-infective therapy within 2 weeks before
randomization or suspected sepsis
o Any medical condition that might not be controlled such as unstable angina,
myocardial infarction within the previous 6 months, unstable congestive heart
failure (NYHA Stage III-IV) or uncontrolled diabetes,
- Electrocardiogram (ECG) with significant modifications suggesting a high risk of
occurrence of an acute clinical event (such as signs of angina pectoris, high risk
arrhythmia, QT/QTc prolongation),
- Prior systemic immunotherapy for advanced or metastatic urothelium carcinoma,
- Prior systemic neoadjuvant/adjuvant chemotherapy that was completed < 6 months
before documented progression,
- Patient who had received any investigational drug within 30 days before randomisation
- History of another malignancy except adequately treated basal carcinoma of the skin, insitu
cervix carcinoma, localised prostate cancer with limited risk of recurrence (pT ≤ 2b,
Gleason score ≤ 7) that did not lead to any other treatment apart from prostatectomy, or
any other tumor with a disease free interval ≥ 5 years,
- Patients who require treatment with ketoconazole, itraconazole, ritonavir, amprenavir,
indinavir, rifampicine (any potent CYP3A4 inhibitor or inducer), phenytoine or
medicinal products known to prolong QT/QTc interval,
- Known hypersensitivity to the study drugs or to drugs with similar chemical structures,
- Any previous organ allograft or any chronic system disease requiring concurrent immune
therapy,
- Woman if pregnant or lactating or with positive pregnancy test at inclusion; woman of
child-bearing potential who did not use or is unwilling or unable to use an acceptable
method to avoid pregnancy during the 2 months preceding the start of study treatment,
for the entire study period and for up to 6 months after the last dose of study treatment,
- Sexually active fertile man not using effective birth control during the study and up to 6
months after the last dose of study treatment if his partner is a woman of childbearing
potential.

E.5 End points

E.5.1

Primary end point(s)

The primary endpoint is to compare the median Progression Free Survival without related Severe Acute Toxicity* between arms (called SAT-PFS).

E.5.1.1

Timepoint(s) of evaluation of this end point

Tumour assessment will be performed according to the RECIST guideline (version 1.1).
Assessment of measurable and non-measurable disease will be carried out at baseline and
every 6 weeks until disease progression.
Survival data and post-study treatments will be reported every 3 months after progression.
Progression and tumour response will be evaluated for all randomized patients by the
investigators.
Duration of disease control and response will be evaluated for all patients with disease
control and responding patients, respectively.
Moreover, clinical parameters such as pain intensity will be assessed every 2 cycles.

E.5.2

Secondary end point(s)

E.5.2.1

Timepoint(s) of evaluation of this end point

as timepoints for primary endpoint evaluation

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

Austria

Belgium

Czech Republic

France

Italy

Poland

Romania

Spain

Taiwan

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 the study period is defined as: 20 months after the accrual of the last patient date
if at least 138 SAT-PFS events have occurred.
Survival information will be collected every 6 weeks until progression and then
approximately every 3 months until death or decision of study closure.

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:

F.1.3

Elderly (>=65 years)

Yes

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

140

F.4.2.2

In the whole clinical trial

162

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)

The treatment and care of the patients after discontinuation of study
participation will be done according to the oncological therapy options
in the particular center at the discretion of the treating physician in
agreement with the patient. To assure continuity, further treatment
will ideally be carried out at the study center. Optionally, it can also be
carried out for example by the family doctor, an oncologist/urologist in
medical practice etc.

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

2016-03-17

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2016-01-13

P. End of Trial
P.	End of Trial Status	Prematurely Ended

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