Clinical Trials Register

Summary
EudraCT Number:	2012-005201-48
Sponsor's Protocol Code Number:	1199.93
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2013-06-03
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

Italy - Italian Medicines Agency

A.2

EudraCT number

2012-005201-48

A.3

Full title of the trial

Double blind, randomised, multicentre, phase II study of nintedanib in combination with pemetrexed / cisplatin followed by continuing nintedanib monotherapy versus placebo in combination with pemetrexed / cisplatin followed by continuing placebo monotherapy for the treatment of patients with unresectable malignant pleural mesothelioma

studio in doppio cieco, randomizzato, di fase II, multicentrico, di Nintedanib in combinazione con Pemetressato/Cisplatino seguito da monoterapia con Nintedanib verso Placebo in combinazione con Pemetressato/Cisplatino seguito da monoterapia con Placebo per il trattamento dei pazienti con mesotelioma pleurico maligno non resecabile.

A.3.1

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

Nintedanib (BIBF 1120) in Mesothelioma

Nintedanib (BIBF 1120) nel Mesotelioma

A.4.1

Sponsor's protocol code number

1199.93

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	Boehringer Ingelheim
B.1.3.4	Country	Italy
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	Boehringer Ingelheim Italia s.p.a.
B.4.2	Country	Italy
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Boehringer Ingelheim Pharma GmbH & Co. KG
B.5.2	Functional name of contact point	QRPE PSC CT Information Disclosure
B.5.3	Address:
B.5.3.1	Street Address	Binger Strasse 173
B.5.3.2	Town/ city	Ingelheim am Rhein
B.5.3.3	Post code	55216
B.5.3.4	Country	Germany
B.5.4	Telephone number	+18002430127
B.5.5	Fax number	+18008217119
B.5.6	E-mail	clintriage.rdg@boehringer-ingelheim.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	BIBF 1120 100 mg capsules
D.3.2	Product code	BIBF 1120
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	Nintedanib
D.3.9.2	Current sponsor code	BIBF 1120
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	100
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	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	BIBF 1120 150 mg capsules
D.3.2	Product code	BIBF 1120
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	Nintedanib
D.3.9.2	Current sponsor code	BIBF 1120
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	150
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
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Capsule, soft
D.8.4	Route of administration of the placebo	Oral use
D.8 Placebo: 2
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Capsule, soft
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Unresectable Malignant Pleural Mesothelioma

pazienti con mesotelioma pleurico maligno non resecabile

E.1.1.1

Medical condition in easily understood language

Cancer of the pleura (the lining covering the lungs) which cannot be treated by surgery

pazienti con mesotelioma pleurico maligno non resecabile

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	16.0
E.1.2	Level	PT
E.1.2	Classification code	10059518
E.1.2	Term	Pleural mesothelioma malignant
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

To evaluate progression free survival measured from the time of randomisation to the time of disease progression or death

L’obiettivo primario dello studio randomizzato, controllato a gruppi paralleli di fase II è di valutare la sicurezza e l’efficacia in termini di sopravvivenza libera da progressione di nintedanib + pemetressato/cisplatino seguito da nintedanib (braccio A) verso placebo + pemetressato/cisplatino seguito da placebo (braccio B) come trattamento di prima linea, per il trattamento dei pazienti con mesotelioma pleurico maligno non resecabile.

E.2.2

Secondary objectives of the trial

To evaluate safety, overall survival and change from baseline in forced
vital capacity (pulmonary function)

Gli obiettivi secondari sono valutare la sopravvivenza globale e valutare i cambiamenti rispetto al basale della capacità vitale forzata in pazienti trattati con il regime nintedanib (braccio A) verso il regime con placebo (braccio B). Inoltre saranno raccolti campioni biologici per la valutazione dei marcatori molecolari e della possibile correlazione con l’esito del trattamento.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

- Histologically confirmed malignant pleural mesothelioma (MPM) (subtype: epithelioid or biphasic)
- Life expectancy of at least 3 months in the opinion of the investigator
- Eastern Cooperative Oncology Group (ECOG) score of 0 or 1
- Measurable disease according to modified Response
Evaluation Criteria In Solid Tumours (RECIST) criteria

1.Pazienti maschi o femmine di età >= 18 anni.
2.Mesotelioma pleurico maligno (sottotipo: epitelioide o bifasico) confermato istologicamente.
3.Aspettativa di vita di almeno 3 mesi, in base al giudizio dello sperimentatore.
4.Punteggio ECOG di 0-1.
5.Malattia misurabile in base ai criteri RECIST modificati.
6.Consenso informato datato e firmato prima dell’inclusione nello studio in accordo alle linee guida ICH-GCP e alle normative locali.

E.4

Principal exclusion criteria

- Previous systemic chemotherapy for MPM
- Prior treatment with nintedanib or any other VEGFR (Vascular Endothelial Growth Factor Receptor) inhibitor
- Patients with sarcomatoid subtype MPM
- Patients with symptomatic neuropathy
- Radiotherapy (except extremities) within 3 months prior to baseline imaging
- Active brain metastases (e.g. stable for < 4 weeks)
- Radiographic evidence of cavitary or necrotic tumours or local invasion of major blood vessels by MPM
- Significant cardiovascular diseases
- Inadequate hematologic, renal, or hepatic function

1.Precedente chemioterapia sistemica per mesotelioma pleurico maligno.
2.Precedente trattamento con nintedanib o qualsiasi altro inibitore VEGFR.
3.Pazienti con mesotelioma pleurico maligno di sottotipo sarcomatoide.
4.Pazienti con neuropatia sintomatica.
5.Pazienti con lieve o moderata insufficienza renale (clearance della creatinina di 45-79mL / minuto), che assumano FANS a breve emivita che non possano o non vogliano interrompere i FANS per un periodo di 5 giorni.
6.Pazienti con lieve o moderata insufficienza renale (clearance della creatinina di 45-79mL / minuto) che assumano FANS a lunga emivita che non possano o non vogliano interrompere i FANS per un periodo di 8 giorni.
7.Ipersensibilita' nota o qualsiasi controindicazione ai farmaci dello studio, compresi pemetressato / cisplatino, ai loro eccipienti o al mezzo di contrasto.
8.Radioterapia (ad eccezione di quella alle estremità) entro i 3 mesi prima della raccolta delle immagini basali (la radioterapia locale per il sollievo dei sintomi e' permessa se effettuata almeno 2 settimane prima della randomizzazione e la malattia misurabile e' al di fuori dell’area sottoposta a radioterapia).
9.Persistenza di tossicita' clinicamente significativa correlata alla radioterapia precedente, a giudizio dello sperimentatore.
10.Pazienti che possano essere eleggibili o che siano considerati eleggibili alla resezione radicale o alla chirurgia di elezione durante il corso dello studio
11.Chirurgia radicale, entro le 4 settimane prima della randomizzazione.
12.Metastasi cerebrali attive.
13.Patologia leptomeningea.
14.Evidenza radiografica (TAC o RMN) di tumori cavitari o necrotici o di invasione locale dei vasi sanguigni maggiori da parte del mesotelioma pleurico maligno.
15.Trattamento con altri farmaci sperimentali o trattamento in un altro studio clinico nelle 4 settimane precedenti l’inizio della terapia o durante il corso dello studio.
16.Terapia anticoagulante (ad eccezione di eparina a basso dosaggio e/o lavaggi con eparina necessari per il mantenimento di un catetere venoso in sede) o terapia antipiastrinica (eccetto terapia a basso dosaggio con acido acetilsalicilico < 325mg al giorno).
17.Traumi maggiori nelle 4 settimane precedenti l’inizio del trattamento con guarigione non completa delle ferite.
18.Storia di eventi emorragici o tromboembolici clinicamente significativi, nei 6 mesi prima dello screening.
19.Nota predisposizione ereditaria al sanguinamento o alla trombosi.
20.Patologie cardiache significative.
21.Proteinuria > 1.0 g/24 ore.22. Bilirubina totale al di sopra del limite superiore della norma (ULN).
23.ALT e / o AST > 1,5 x ULN in pazienti senza metastasi epatiche.
ALT e / o AST > 2,5 x ULN in pazienti con metastasi epatiche.
24.Rapporto internazionale normalizzato (INR) > 2.
25.Tempo di protrombina PT e/o tempo di tromboplastina parziale PTT con deviazione > 50% daULN.
26.Conta assoluta dei neutrofili (ANC) < 1.500/µl (1,5x109/L).
27.Piastrine < 100.000/mcrl (100x109/L).
28.Emoglobina < 9 g/dl o valori che richiedano trasfusioni.
29.Clearance della creatinina < 45 mL/min calcolata con la formula di Cockcroft e Gault (come sotto indicato) o Tasso di Filtrazione Glomerulare (GFR), misurato tramite il metodo della creatinina serica Tc99m-DPTA (si veda la sinossi per la formula).
30.Altre patologie maligne nei tre anni precedenti lo screening, ad eccezione del carcinoma basale della pelle o il carcinoma in situ della cervice.
31.Infezioni gravi attive, in particolare che richiedano terapia sistemica antibiotica o antimicrobica.
32.Nota infezione attiva o cronica da epatite C e/o B.
33.Disordini gastrointestinali o anomalie che potrebbero interferire con l’assorbimento del farmaco in studio.
34.Patologie concomitanti gravi o non oncologiche come malattie neurologiche, psichiatriche, infettive o ulcere attive (tratto gastro intestinale, cute) o anomalie di laboratorio che potrebbero aumentare il rischio connesso con la partecipazione allo studio o la somministrazione del farmaco e che a giudizio dello sperimentatore determinino l’ineleggibilità del paziente allo studio.
35.Pazienti che siano sessualmente attivi e che si rifiutino di utilizzare un metodo contraccettivo efficace durante lo studio, e per almeno tre mesi dopo la conclusione di nintedanib/placebo e per almeno dodici mesi dopo la cessazione della chemioterapia.
36.Gravidanza o allattamento.
37.Fattori psicologici, familiari, sociali o geografici che potenzialmente possano compromettere l’aderenza al protocollo di studio e al follow-up programmato.
38.Abuso attivo di alcool o farmaci.

E.5 End points

E.5.1

Primary end point(s)

1. Progression free survival measured from the time of randomisation to the time of disease progression or death of any cause, whichever occurs earlier

1. Sopravvivenza libera da progressione, calcolata dalla randomizzazione fino alla progressione o decesso per qualsiasi causa, qualunque evento si verifichi per primo.

E.5.1.1

Timepoint(s) of evaluation of this end point

1. up to 3 years

1. fino a 3 anni

E.5.2

Secondary end point(s)

1. Overall survival measured from the time of randomisation to the time of death of any cause
2. Change from baseline in forced vital capacity (pulmonary function)

1. Sopravvivenza globale, calcolata dalla randomizzazione fino al decesso per qualsiasi causa.
2. Cambiamenti nella capacità vitale forzata (funzione polmonare) rispetto al basale.

E.5.2.1

Timepoint(s) of evaluation of this end point

1. up to 4 years

2. up to 3 years

1. fino a 4 anni
2. fino a 3 anni

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

Yes

E.6.12

Pharmacoeconomic

E.6.13

Others

Yes

E.6.13.1

Other scope of the trial description

Biomarkers

Biomarker

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

Australia

Canada

Denmark

France

Germany

Italy

United Kingdom

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

The trial will be considered completed 18 months after the last patient was randomised. The primary analysis of PFS will be conducted and reported when approximately 65 patients have progressed or died. However, it may also be performed with fewer events within approximately 27 months total trial duration. If patients are still ongoing or in follow-up at the time of the clinical trial report for PFS, the clinical trial database will be kept open to collect the additional data.

Lo studio sara’ considerato completato 18 mesi dopo la randomizzazione dell’ultimo paziente. L'analisi primaria della PFS sara’ effettuata quando circa 65 pazienti saranno in progressione di malattia o deceduti. Tuttavia, l'analisi potra’ anche essere eseguita con meno eventi entro circa 27 mesi (durata totale della sperimentazione). Se i pazienti saranno ancora in trattamento o in follow-up al momento del report per la PFS, il database sara’ mantenuto aperto per raccogliere i dati addizionali

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

F.4.2.2

In the whole clinical trial

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)

Patients will be treated in the trial until cancer progression or undue toxicity. Follow-up treatment after disease progression is at the discretion of the treating physician according to local standard of care.
If the trial is ended by the sponsor for any reason, patients still being treated with a clinical benefit will be offered treatment in a follow-up trial. In case the trial is terminated by the sponsor for safety reasons, patients will not continue treatment with the trial drug.

I pazienti saranno trattati in studio fino a progressione o tossicità eccessiva. Il trattamento dopo progressione e' a discrezione del p.i., secondo gli standard locali. Se lo studio sarà terminato dallo sponsor per qualsiasi motivo, ai pazienti ancora in trattamento con beneficio clinico sarà offerto un trattamento in uno studio di follow-up. Nel caso lo studio venga concluso dallo sponsor per motivi di sicurezza, i pazienti non continueranno il trattamento con il farmaco sperimentale.

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

2013-11-04

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2013-06-12

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

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