Clinical Trials Register

Summary
EudraCT Number:	2012-004295-19
Sponsor's Protocol Code Number:	1209-EnTF
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2015-07-31
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

Spain - AEMPS

A.2

EudraCT number

2012-004295-19

A.3

Full title of the trial

A phase II study exploring the safety and efficacy of nintedanib (BIBF1120) as second line therapy for patients with either differentiated or medullary thyroid cancer progressing after first line therapy.

Un estudio de fase II para investigar la seguridad y eficacia del nintedanib (BIBF1120) como terapia de segunda línea para pacientes con cáncer diferenciado o medular de tiroides con progreso tras la terapia de primera línea.

A.3.1

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

A phase II study of second line therapy on safety and efficacy of nintedanib for patients with either differentiated or medullary thyroid cancer progressing after first line therapy.

A.3.2

Name or abbreviated title of the trial where available

EORTC protocol 1209-EnTF

A.4.1

Sponsor's protocol code number

1209-EnTF

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT01788982

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	European Organisation for Research and Treatment of Cancer. EORTC
B.1.3.4	Country	Belgium
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	Boehringer Ingelheim
B.4.2	Country	France
B.4.1	Name of organisation providing support	EORTC
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	European Organisation for the Research and Treatment of Cancer
B.5.2	Functional name of contact point	Clinical Operations Department
B.5.3	Address:
B.5.3.1	Street Address	Avenue E. Mounier, 83/11
B.5.3.2	Town/ city	Brussels
B.5.3.3	Post code	1200
B.5.3.4	Country	Belgium
B.5.4	Telephone number	+322774 1510
B.5.5	Fax number	+322774 1030
B.5.6	E-mail	regulatory@eortc.be

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	Vargatef
D.2.1.1.2	Name of the Marketing Authorisation holder	Boehringer Ingelheim International Gmbh
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	nintedanib 100
D.3.2	Product code	BIBF1120
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 (for free base)
D.3.9.1	CAS number	656247-17-5
D.3.9.2	Current sponsor code	BIBF 1120
D.3.9.3	Other descriptive name	NINTEDANIB 100
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	Yes
D.2.1.1.1	Trade name	Vargatef
D.2.1.1.2	Name of the Marketing Authorisation holder	Boehringer Ingelheim International Gmbh
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	nintedanib 150
D.3.2	Product code	BIBF1120
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 (for free base)
D.3.9.1	CAS number	656247-17-5
D.3.9.2	Current sponsor code	BIBF 1120
D.3.9.3	Other descriptive name	NINTEDANIB 150
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

Histologically confirmed differentiated or medullary thyroid cancer by local pathologist.

Cáncer diferenciado o medular de tiroides confirmado histológicamente por el patólogo local.

E.1.1.1

Medical condition in easily understood language

Patient with Thyroid cancer

Cáncer de tiroides

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	18.0
E.1.2	Level	PT
E.1.2	Classification code	10027105
E.1.2	Term	Medullary thyroid cancer
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

E.1.2 Medical condition or disease under investigation

E.1.2	Version	18.0
E.1.2	Level	PT
E.1.2	Classification code	10066474
E.1.2	Term	Thyroid cancer
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

E.1.2 Medical condition or disease under investigation

E.1.2	Version	18.0
E.1.2	Level	PT
E.1.2	Classification code	10033701
E.1.2	Term	Papillary thyroid 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

The primary objective is to explore the efficacy of nintedanib (as measured by progression free survival) as second line therapy for patients with either differentiated or medullary thyroid cancer progressing after first line therapy.

El objetivo principal es explorar la eficacia del nintedanib (según la medición de la supervivencia sin avance de la enfermedad) como terapia de segunda línea para pacientes con cáncer diferenciado o medular de tiroides con progreso tras la terapia de primera línea.

E.2.2

Secondary objectives of the trial

? To explore the safety of nintedanib as second line treatment in patients with MTC or DTC.

? To explore the molecular mechanisms of action of the drug.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

? Histologically confirmed differentiated or medullary thyroid cancer by local pathologist.
? Available tumor tissue at the time of initial diagnosis for histology review.
? Locally advanced or metastatic disease deemed incurable by surgery, radiotherapy and/or radioactive iodine (RAI).
? Patients must have measurable lesion with documented progression during the 12 months prior to randomization.
? Patients must have received one or 2 prior line of treatment (but no more than two) and must be off treatment for at least 4 weeks prior to randomization. Patients with an MTC must have received one or 2 prior line of treatment (but no more than two) and must be off treatment for at least 4 weeks prior to randomization. If it is available and reimbursed in the respective country one of the prior lines of treatment needs to be with Vandetanib as long as there is no contraindication or the patient refuses the treatment with Vandetanib.
? Age ?18 years.
? Performance status (PS) 0-1 (WHO, Appendix C).
? Life expectancy of more than 12 weeks.
? Adequate organ function, evidenced by the following laboratory results within 3 weeks prior to randomization

?Cáncer diferenciado o medular de tiroides confirmado histológicamente por el patólogo local.
?Tejido tumoral disponible en el momento del diagnóstico inicial para revisión histológica. Proporcionar el tejido tumoral para revisión histológica es obligatorio para cada centro.
?Enfermedad avanzada a nivel local o metastásica considerada incurable con cirugía, radioterapia o RAI.
?Los pacientes deben tener una lesión mensurable con progresión documentada durante los 12 meses anteriores a la aleatorización, de conformidad con RECIST V.1.1. Los pacientes que fueron retirados del tratamiento de primera línea debido a la toxicidad sin progresión de enfermedad documentada o que han recibido placebo (en el contexto de un ensayo clínico) como tratamiento anterior no cumplen los requisitos para participar.
?Los pacientes deben haber recibido una o dos líneas previas de tratamiento (pero no más de dos) y deben no recibir tratamiento durante al menos cuatro semanas antes de la asignación aleatoria. Los pacientes con MTC [Carcinoma Medular de Tiroides] deben recibir una o dos líneas anteriores de tratamiento (pero no más de dos) y deben no recibir tratamiento por lo menos 4 semanas antes de la asignación aleotoriaaleatoria. Si está disponible y es reembolsado en el país respectivo, una de las líneas anteriores de tratamiento debe ser con Vandetanib mientras no exista ninguna contraindicación ni el paciente rechace el tratamiento con Vandetanib.?
?Edad >18 años
?Estado funcional (PS) 0-1 (WHO, Anexo C)
?Esperanza de vida de más de 12 semanas.
?Función orgánica adecuada, comprobada por los siguientes resultados de laboratorio tres semanas antes de la asignación aleatoria

E.4

Principal exclusion criteria

? Current symptomatic brain metastases or if previously present, must have been treated at least two months before randomization.
? History of other malignancy within the last 5 years, except for adequately treated carcinoma in situ of the cervix or basal cell or spinocellular carcinoma of the skin.
? Ongoing treatment related toxicity due to prior treatment > grade I (except alopecia).
? History of significant cardiac disease
? Current uncontrolled hypertension
? Evidence of active bleeding or bleeding diathesis.
? Cerebrovascular accident at any time in the past, transient ischemic attack, deep venous thrombosis (DVT) or pulmonary embolism in the past 6 months
? History of clinically significant gastrointestinal disorders .
? Current severe, uncontrolled systemic disease or any other systemic disease/symptom that can hamper compliance with the protocol.
? Major surgical procedure or significant traumatic injury within 28 days prior to randomization or anticipation of the need for major surgery.
? History of receiving any investigational treatment within 28 days prior to randomization
? Women or patients of child bearing potential who do not use any contraceptive methods
? Any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule.
? Hypersensitivity to nintedanib, peanut or soya, or to any of the excipients of nintedanib.

?No presentar actualmente metástasis sintomáticas en el cerebro, o de haber presentado anteriormente, deben haber sido tratadas durante al menos dos meses antes de la asignación aleatoria. Una TC o una IRM del cerebro es obligatoria (en un plazo de 4 semanas antes de la asignación aleatoria) para evaluar la presencia de metástasis en el cerebro.
?No presentar historial de otra malignidad en los últimos 5 años, excepto por carcinoma adecuadamente tratado in situ del cuello uterino o células basales o carcinoma espinocelular de la piel.
?No hay un tratamiento en curso relacionado con la toxicidad derivada del primer tratamiento >grado I excepto alopecia)
?No presentar historial de enfermedad cardíaca significativa
?No presentar hipertensión no controlada actual
? No existen evidencias de sangrado activo o diátesis hemorrágica.
? No haber sufrido un accidente cerebrovascular en el pasado, ataque isquémico transitorio, trombosis venosa profunda (TVP) o embolia pulmonar en los últimos seis meses.
? No se permite la anticoagulación terapéutica (excepto heparina en dosis baja o solución heparinizada según sea necesario para el mantenimiento de un dispositivo intravenoso permanente) o terapia antiplaquetas (excepto para la terapia de bajas dosis con ácido acetilsalicílico < 325mg por día).
? No presentar hipersensibilidad a nintedanib, a los cacahuetes o a la soja, ni a ninguno de los excipientes de nintedanib.
? No presentar historial de trastornos gastrointestinales clínicamente significativos, incluido lo siguiente: síndrome de mala absorción, resección mayor del estómago o del intestino delgado que pudiera afectar la absorción del fármaco del estudio, úlcera péptica activa, lesiones intraluminales metastásicas conocidas con riesgo de hemorragia, enfermedad inflamatoria intestinal, colitis ulcerosa u otros trastornos
digestivos que comporten un aumento del riesgo de perforación. No presentar historial de fístula abdominal, perforación gastrointestinal o absceso intraabdominal en los 28 días anteriores al comienzo del tratamiento del estudio.
?No presentar enfermedad sistémica no controlada grave (por ej., insuficiencia cardiovascular, pulmonar o metabólica significativa clínicamente; problemas de cicatrización; úlceras; o fracturas óseas, infección conocida con VIH, hepatitis B activa o virus de hepatitis C) u otras enfermedades/síntomas sistémicos que puedan afectar al cumplimiento del protocolo, a criterio de los médicos.
?No presentar procedimiento quirúrgico importante o lesión trumática significativa en los 28 días anteriores a la asignación aleatoria o previsión de la necesidad de una cirugía importante durante el transcurso del tratamiento o la presencia de una lesión, fractura o úlcera que no cicatriza.
?No presentar historial de recibir tratamiento de investigación en los 28 días anteriores a la asignación aleatoria.

E.5 End points

E.5.1

Primary end point(s)

? Progression free survival (RECIST 1.1)

Supervivencia libre de progresión (RECIST 1.1)

E.5.1.1

Timepoint(s) of evaluation of this end point

Patients be followed every 8 weeks until progression for the endpoints of the trial

E.5.2

Secondary end point(s)

? Response Rate (RECIST 1.1)
? Toxicity profile
? Duration of response
? Exploration of the molecular mechanisms of action of drug

?Tasa de respuesta (RECIST 1.1)
?Perfil de toxicidad
?Duración de la respuesta
?Exploración de los mecanismos moleculares de acción del fármaco

E.5.2.1

Timepoint(s) of evaluation of this end point

Patients be followed every 8 weeks until progression for the endpoints of the trial

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

Yes

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

E.8.6.2

Trial being conducted completely outside of the EEA

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

End of study occurs when all of the following criteria have been satisfied:
1. Thirty days after all patients have stopped protocol treatment
2. The trial is mature for the analysis of the primary endpoint as defined in the protocol
3. The database has been fully cleaned and frozen for this analysis

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.1.1.1

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

143

F.4.2.2

In the whole clinical trial

143

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)

Follow-up/observation will be done 4 weeks (+/- 1 week) after the last treatment administration (study medication).
? In case of treatment-related toxicity, follow-up for safety will be done every 4 weeks (+/- 1 week) until resolution or up to six months.
? In case patients in the placebo arm cross-over to nintedanib after documented progression (according to RECIST 1.1), follow-up

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

2015-09-10

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2015-08-26

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2019-08-28

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