Clinical Trials Register

Summary
EudraCT Number:	2012-000095-42
Sponsor's Protocol Code Number:	1199.52
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2014-07-03
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

2012-000095-42

A.3

Full title of the trial

A double-blind, randomised, placebo controlled Phase III study of nintedanib plus best supportive care (BSC) versus placebo plus BSC in patients with colorectal cancer refractory to standard therapies.

Studio di fase III in doppio cieco, randomizzato, con nintedanib in aggiunta alle migliori terapie di supporto (BSC), controllato verso placebo più BSC, in pazienti con carcinoma del colon retto refrattario alle terapie standard.

A.3.1

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

Nintedanib (BIBF 1120) vs placebo in refractory colorectal cancer

Nintedanib (BIBF 1120) vs placebo in pazienti con carcinoma del colon retto refrattario

A.3.2

Name or abbreviated title of the trial where available

LUME-Colon 1

A.4.1

Sponsor's protocol code number

1199.52

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 Italia S.p.A.
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	Nintedanib 100 mg soft 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.3.9.3	Other descriptive name	NINTEDANIB
D.3.9.4	EV Substance Code	SUB120728
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	Nintedanib 150 mg soft 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.3.9.3	Other descriptive name	NINTEDANIB
D.3.9.4	EV Substance Code	SUB120728
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

Patients with metastatic colorectal cancer refractory to standards therapies

pazienti con carcinoma del colon retto refrattario alle terapie standard

E.1.1.1

Medical condition in easily understood language

metastatic colorectal cancer

carcinoma del colon retto

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	17.0
E.1.2	Level	LLT
E.1.2	Classification code	10052362
E.1.2	Term	Metastatic colorectal 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 objective of this Phase III study is to evaluate the efficacy and safety of nintedanib in patients with mCRC after failure of previous treatment with standard chemotherapy and biological agents.

L’obiettivo di questo studio di fase III è quello di valutare l’efficacia e la sicurezza di nintedanib in pazienti con carcinoma del colon-retto metastatico dopo fallimento con precedente trattamento con chemioterapia standard e agenti biologici.

E.2.2

Secondary objectives of the trial

Secondary objectives are Objective tumour response, disease control, quality of life and safety.

Risposta oggettiva, controllo di malattia, qualita’ di vita e profilo di sicurezza

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

- Age >= 18 years
- Signed informed consent
- Histologically or cytologically confirmed colorectal adenocarcinoma
- Metastatic or locally advanced disease not amenable to curative surgery and/or radiotherapy
- Eastern Cooperative Oncology Group (ECOG) performance status <= 1
- At least one measurable lesion according to Response Evaluation Criteria In Solid Tumours (RECIST) version 1.1
- Progression on standard therapies or withdrawn from standard treatment due to unacceptable toxicity. Previous standard treatment must include all of the following:
- - fluoropyrimidine
- - oxaliplatin: Patients treated with oxalipatin in adjuvant setting should have progressed within 6 months of completion of adjuvant therapy or they must have been treated with oxaliplatin for metastatic disease
- - irinotecan
- - bevacizumab or aflibercept
- - cetuximab or panitumumab for patients with K-Ras wt or Ras wt tumours
- - previous treatment with regorafenib is allowed
- - Life expectancy of at least 12 weeks
- - Hepatic function: aspartate aminotransferase (AST)/ Alanine Amino Tranferase (ALT) <= 1.5 X Upper Limit of Normal (ULN) and bilirubin <= ULN for patients without liver metastases. AST/ALT <= 2.5 X ULN and bilirubin <= ULN for patients with liver metastases. Patients with Gilbert syndrome and bilirubin < 2 X ULN and normal AST/ALT are eligible
- Coagulation parameters: International normalised ratio (INR) < 2 and prothrombin Time (PTT) <= 2xULN

1.Eta' >= 18 anni
2.Firma del consenso informato
3.Adenocarcinoma del colon retto confermato istologicamente o citologicamente
4.Malattia metastatica o localmente avanzata non eleggibile a chirurgia curativa e/o radioterapia.
5.ECOG Performance Status <= 1.
6.Almeno una lesione misurabile secondo criteri RECIST 1.1.
7.Progressione alle terapie standard o interruzione delle terapie standard per tossicità inaccettabile. Le precedenti terapie standard devono includere:
-Fluoropirimidine
-Oxaliplatino: i pazienti trattati con oxaliplatino nel setting adiuvante devono essere progrediti entro 6 mesi dal completamento della terapia adiuvante, o devono essere stati trattati con oxaliplatino per la malattia metastatica
-Irinotecan
-Bevacizumab o aflibercept
-Cetuximab o panitumumab in pazienti con tumori K-Ras wt o Ras wt
8.La terapia standard disponibile rimanente, raccomandata dallo sperimentatore, è la miglior terapia di supporto (BSC) (nota: il precedente trattamento con regorafenib è permesso, se disponibile, secondo gli standard locali e l’opinione dello sperimentatore).
9.Minimo intervallo di tempo di 3 settimane, tra l’ultima somministrazione di un trattamento per il carcinoma del colon-retto (agenti citotossici o target) e la randomizzazione.
10.Aspettativa di vita di almeno 12 settimane.
11.Creatinina serica <= 1.5 x ULN.
12.Proteinuria <= grado 2 secondo CTCAE.
13.Funzionalità epatica: AST/ALT <= 1.5 x ULN e bilirubina <= ULN, per pazienti senza metastasi epatiche. AST/ALT <= 2.5 x ULN e bilirubina <= ULN, per pazienti con metastasi epatiche. Pazienti con sindrome di Gilbert e bilirubina < 2 x ULN e valori normali di AST/ALT sono eleggibili.
14.Conta assoluta dei neutrofili (ANC) >= 1500 neutrofili/ µL, piastrine >= 85.000/ µL, emoglobina >= 9 g/dL.
15.Parametri di coagulazione: rapporto internazionale normalizzato (INR) < 2 e tempo di protrombina (PTT) <= 2 x ULN.

E.4

Principal exclusion criteria

- Previous treatment with nintedanib
- toxicity attributed to previous anticancer therapy that did not resolve to Common Terminology Criteria for Adverse Events (CTCAE) grade <=1
- History of other malignancies in the last 5 years, in particular those that could interfere with interpretation of results.
- Serious concomitant disease or medical condition affecting compliance with trial requirements or which are considered relevant for the evaluation of the efficacy or safety of the trial drug,
- Significant cardiovascular diseases
- History of severe haemorrhagic or thromboembolic event in the past 12 months
- Bleeding or thrombotic disorders requiring anticoagulant therapy such as warfarin, or similar agents requiring therapeutic INR monitoring
- Gastrointestinal disorders or abnormalities that would interfere with absorption of study drug
- Patient with brain metastases that are symptomatic and/or require therapy.
- Patients of childbearing potential who are sexually active and unwilling to use a highly effective method of contraception
- Pregnancy or breast-feeding.

1.Precedente trattamento con nintedanib.
2.Nota ipersensibilità ai farmaci sperimentali o ai loro eccipienti
3.Tossicità attribuita a precedente chemioterapia che non sia regredita ad un grado CTCAE <= 1, eccetto emoglobina, alopecia, pigmentazione e neurotossicità correlata ad oxaliplatino.
4.Storia clinica di altre neoplasie nei 5 anni precedenti, in particolare quelle che possano interferire con l’interpretazione dei risultati. Sono eleggibili i pazienti con carcinoma della pelle basocellulare o squamocellulare adeguatamente trattati o con carcinoma della cervice e altri tipi di cancro in stadio precoce trattati con intento curativo.
5.Malattie concomitanti gravi o condizioni mediche che influenzino la compliance ai requisiti dello studio o che siano considerati rilevanti per la valutazione dell’efficacia o della sicurezza del farmaco sperimentale, come malattie neurologiche, psichiatriche, infettive o ulcere attive (del tratto gastro-intestinale, della pelle) o valori anormali di laboratorio che possano aumentare il rischio associato alla partecipazione allo studio o alla somministrazione del farmaco sperimentale, e che, secondo il giudizio dello sperimentatore, rendano inappropriata la partecipazione allo studio per il paziente.
6.Ferite di grave entità e/o interventi chirurgici o fratture ossee nelle 4 settimane precedenti l’inclusione nello studio, o procedure chirurgiche pianificate durante il periodo di studio.
7.Malattie cardiovascolari significative (per esempio ipertensione incontrollata, angina instabile, storia di infarto del miocardio nei 6 mesi precedenti l’inclusione nello studio, insufficienza cardiaca congestizia > NYHA II)
8.Storia di eventi emorragici o tromboembolici gravi nei 12 mesi precedenti (con l’esclusione di trombosi da catetere venoso centrale e trombosi venosa profonda periferica). Nota predisposizione ereditaria a sanguinamento o a trombosi.
9.Sanguinamento o disturbi trombotici che necessitino terapia anticoagulante come warfarin o agenti simili che richiedano il monitoraggio di INR (è permesso il trattamento con eparina a basso peso molecolare e/o lavaggio con eparina per il mantenimento di un dispositivo intravenoso interno).
10.Malattia infiammatoria intestinale e altre condizioni mediche gravi che aumentino il rischio di perforazione o sanguinamento, secondo il giudizio dello sperimentatore.
11.Disturbi o anomalie gastrointestinali che interferiscano con l’assorbimento del farmaco sperimentale.
12.Pazienti con metastasi cerebrali che siano sintomatiche e/o richiedano terapia.
13.Abuso attivo di alcool o droghe
14.Pazienti in grado di procreare, che siano sessualmente attivi e che non siano disposti a usare un metodo di contraccezione altamente efficace (per esempio impianti di contraccezione, iniettabili, contraccettivi orali combinati, dispositivi intrauterini o vasectomia del partner per le pazienti di sesso femminile, un metodo a doppia barriera quale preservativo più diaframma con spermicida per i pazienti di sesso maschile) durante lo studio e per almeno tre mesi dopo la conclusione del trattamento con nintedanib. I pazienti saranno considerati in grado di procreare a meno che non siano stati sterilizzati chirurgicamente con isterectomia o chiusura bilaterale delle tube/salpingectomia, o siano in menopausa da almeno 2 anni.
15.Gravidanza o allattamento al seno
16.Pazienti non in grado di essere complianti con il protocollo

E.5 End points

E.5.1

Primary end point(s)

1: Primary endpoint is progression free survival (PFS)

1) Sopravvivenza libera da progressione (PFS)

E.5.1.1

Timepoint(s) of evaluation of this end point

1: 22 months

1) 22 mesi

E.5.2

Secondary end point(s)

1: Key secondary endpoint is Overall survival (OS)

2: Objective tumour response

3: Disease control

1) L’endpoint secondario chiave è la sopravvivenza globale (OS)
2) Risposta oggettiva
3) Controllo di malattia

E.5.2.1

Timepoint(s) of evaluation of this end point

1: 22 months

2: 22 months

3: 22 months

1) 22 mesi
2) 22 mesi
3) 22 mesi

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

Yes

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

Yes

E.6.11

Pharmacogenomic

Yes

E.6.12

Pharmacoeconomic

Yes

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

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

Argentina

Australia

Austria

Belgium

Canada

Czech Republic

Denmark

France

Germany

Hong Kong

Israel

Italy

Japan

Korea, Republic of

Luxembourg

Mexico

Netherlands

Poland

Portugal

Russian Federation

Singapore

Spain

Sweden

Taiwan

Turkey

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 end of the trial will occur when the last patient completes his/her REP period and the required number of OS events has occurred

La fine della sperimentazione è definita quando l'ultimo paziente ha completato il suo “Residual Effect Period” (REP) ed il numero di eventi OS sarà raggiunto

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

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

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)

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:

500

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

264

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

396

F.4.2.2

In the whole clinical trial

800

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 randomised patients will be treated until unequivocal progression or undue toxicity; no other anti-cancer treatment will be allowed until study medication is discontinued. End of treatment, regardless of the reason of EOT, will be followed by a Residual Effect Period (REP) which starts from last treatment intake and ends 28 days later.

I pazienti randomizzati saranno trattati fino ad una inequivocabile progressione o ad una eccessiva tossicità; nessun altro trattamento anti-tumorale sarà consentito fino a interruzione del farmaco in studio. La fine del trattamento, indipendentemente dal motivo di EOT, sarà seguita da un “Residual Effect Period” (REP), che partirà dall’ultima assunzione del trattamento e terminerà 28 giorni dopo.

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

2014-09-29

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2014-07-16

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2016-09-15

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