Clinical Trials Register

Summary
EudraCT Number:	2014-000579-20
Sponsor's Protocol Code Number:	CINC280X2104
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Temporarily Halted
Date on which this record was first entered in the EudraCT database:	2014-06-09
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

2014-000579-20

A.3

Full title of the trial

A phase Ib, open-label, multicenter, dose escalation and expansion study, to evaluate the safety, pharmacokinetics and activity of INC280 in combination with cetuximab in c-MET positive CRC and HNSCC patients who have progressed after anti-EGFR monoclonal antibody therapy

Estudio fase Ib, abierto, multicéntrico, de escalada de dosis y de expansión de dosis, para evaluar la seguridad, la farmacocinética y la actividad de INC280 en combinación con cetuximab, en pacientes con CCR y CCECC con c-MET positivo que han progresado después de terapia con anticuerpo monoclonal anti-EGFR

A.3.1

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

A study with INC280 in combination with cetuximab in selected patients with colorectal or head and neck cancer who have progressed on prior therapy

Estudio de seguridad y de eficacia de INC280 y de cetuximab, en pacientes adultos con CCRm y CCECC con c-MET positive después de progresión con cetuximab o panitumumab

A.4.1

Sponsor's protocol code number

CINC280X2104

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	Novartis Farmacéutica, S.A.
B.1.3.4	Country	Spain
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	Novartis Pharma Services AG
B.4.2	Country	Switzerland
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Novartis Farmacéutica, S.A.
B.5.2	Functional name of contact point	Departamento Médico Oncología (GMO)
B.5.3	Address:
B.5.3.1	Street Address	Gran Vía de les Corts Catalanes, 764
B.5.3.2	Town/ city	Barcelona
B.5.3.3	Post code	08013
B.5.3.4	Country	Spain
B.5.4	Telephone number	34900353036
B.5.5	Fax number	34932479903
B.5.6	E-mail	eecc.novartis@novartis.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	INC280 200 mg
D.3.2	Product code	INC280
D.3.4	Pharmaceutical form	Film-coated tablet
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	Not available
D.3.9.1	CAS number	INC280
D.3.9.2	Current sponsor code	INC280
D.3.9.3	Other descriptive name	INC280
D.3.9.4	EV Substance Code	SUB31645
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: 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	INC280 50 mg
D.3.2	Product code	INC280
D.3.4	Pharmaceutical form	Film-coated tablet
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	Not available
D.3.9.1	CAS number	INC280
D.3.9.2	Current sponsor code	INC280
D.3.9.3	Other descriptive name	INC280
D.3.9.4	EV Substance Code	SUB31645
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	50
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	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	Erbitux
D.2.1.1.2	Name of the Marketing Authorisation holder	Merck KGaA
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	Erbitux 5mg/mL
D.3.4	Pharmaceutical form	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	CETUXIMAB
D.3.9.1	CAS number	205923-56-4
D.3.9.2	Current sponsor code	CETUXIMAB
D.3.9.3	Other descriptive name	Erbitux
D.3.9.4	EV Substance Code	SUB01178MIG
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	5
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

Head and neck squamous cell carcinoma.
Colorectal cancer.

Carcinoma escamoso de cabeza y cuello.
Cáncer colorrectal metastásico.

E.1.1.1

Medical condition in easily understood language

Head and neck cancer
Colorectal cancer

Cáncer colorrectal
Cáncer de cabeza y cuello

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	PT
E.1.2	Classification code	10060121
E.1.2	Term	Squamous cell carcinoma of head and neck
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	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	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 estimate the MTD and/or RDE of INC280 in combination with cetuximab in c-MET positive mCRC and HNSCC patients as measured by the incidence of DLTs in Cycle 1.

Calcular la DMT y/o DRE de INC280 en combinación con cetuximab en
pacientes con CCRm y CCECC con c-MET positivo, medida con la incidencia de TLDs en el Ciclo 1.

E.2.2

Secondary objectives of the trial

1. To characterize the safety and tolerability of the INC280 and cetuximab combination as measured by the frequency and severity of AEs/SAEs and the frequency of dose interruptions and dose reductions in patients treated with the combination of INC280 and cetuximab.
2. To assess preliminary anti-tumor activity of the INC280 and cetuximab combination as measured by Overall Response Rate and Progression Free Survival in patients treated with the combination of INC280 and cetuximab.
3. To assess additional clinical activity of the INC280 and cetuximab combination as measured by Overall Survival for patients in the expansion part of the study.
4. To characterize the PK profile of INC280 with cetuximab combination as measured by time versus plasma concentration profiles and basic PK parameters of INC280.

1. Caracterizar la seguridad y tolerabilidad de la combinación de INC280 y cetuximab, medida con la frecuencia y severidad de AAs/AAGs y la frecuencia de interrupciones de la dosis y de reducciones de la dosis en pacientes tratados con la combinación de INC280 y cetuximab.
2. Evaluar la actividad antitumoral preliminar de la combinación de INC280 y de cetuximab medida con la tasa de respuesta global y la supervivencia libre de progresión en pacientes tratados con la combinación de INC280 y cetuximab.
3. Evaluar la actividad clínica adicional de la combinación de INC280 y
cetuximab medida con la supervivencia global en pacientes de la parte de expansión del estudio.
4. Caracterizar el perfil PK de INC280 en combinación con cetuximab, medido con los perfiles de concentración plasmática frente a tiempo y con los parámetros básicos PK de INC280.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Male or female aged greater than or equal to 18 years.
2. Metastatic colorectal cancer or head and neck squamous cell carcinoma.
3. c-MET positive (defined by c-MET IHC intensity score +2 or +3 in greater than or equal to 50% of tumor cells) and K/NRAS-WT status for mCRC patients only.
4. At least one previous line of treatment for the metastatic disease and the last treatment must have included cetuximab or panitumumab. Documentation of clinical benefit and subsequent progression on cetuximab or panitumumab treatment is required for patients in the expansion part.
5. Measurable disease as per RECIST v1.1.
6. ECOG performance status ? 2.

1. Hombres y mujeres con edad mayor o igual a 18 años.
2. Cáncer colorrectal metastásico o carcinoma escamoso de cabeza y cuello.
3. Estado de c-MET positivo (definido con puntuación de intensidad +2 o +3 en IHC de c-MET en mayor o igual a 50% de las células del tumor) y estado de K/NRAS-WT sólo para pacientes con CCRm.
4. Por lo menos una línea previa de tratamiento para la enfermedad metastásica y el último tratamiento deberá haber incluido cetuximab o panitumumab. Se requiere documentación de beneficio clínico y progresión posterior con cetuximab o panitumumab para pacientes de la parte de expansión.
5. Enfermedad medible según los RECIST v1.1.
6. Estado funcional del ECOG ? 2.

E.4

Principal exclusion criteria

1. Prior treatment with c-MET/HGF or EGFR inhibitors (with the exception of the last treatment).
2. History of severe reactions to cetuximab and/or panitumumab (except for G3 rash and G3 hypomagnesaemia).
3. History of acute or chronic pancreatitis.
4. Active bleeding within 4 weeks prior to screening visit.
5. Symptomatic brain metastases.
6. Feeding tube dependence.
7. Not adequate hematologic, renal and hepatic function.

1. Tratamiento previo con inhibidores de c-MET/HGF o de EGFR (con la excepción del último tratamiento).
2. Antecedentes de reacciones severas a cetuximab y/o panitumumab (excepto para erupción de G3 y hipomagnesemia de G3).
3. Historial de pancreatitis aguda o crónica.
4. Hemorragia activa dentro de las 4 semanas antes de la visita de selección.
5. Metástasis cerebrales sintomáticas.
6. Dependencia de alimentación por sonda.
7. Función hematológica, renal y hepática no adecuada.

E.5 End points

E.5.1

Primary end point(s)

Incidence of DLTs

Incidencia de TLDs

E.5.1.1

Timepoint(s) of evaluation of this end point

Assessed during cycle 1 of treatment with INC280 and cetuximab

Evaluadas durante el ciclo 1 del tratamiento con INC280 y cetuximab.

E.5.2

Secondary end point(s)

1) Safety: Frequency and severity of AEs/SAEs
Tolerability: Frequency of dose interruptions and dose reductions
2) ORR and PFS per response evaluation criteria in solid tumors (RECIST) v1.1
3) OS (only in Expansion part)
4) Plasma concentration versus time profiles and basic PK parameters of INC280

1) Seguridad: frecuencia y severidad de AAs/AAGs.
Tolerabilidad: frecuencia de interrupciones y de reducciones de la dosis.
2) La TRG y la SLP según los criterios de evaluación de respuesta en tumores sólidos (RECIST) v1.1
3) SG.
4) Concentración plasmática frente a perfiles de tiempo y parámetros PK básicos de INC280.

E.5.2.1

Timepoint(s) of evaluation of this end point

1) Assessed from C1D1 until treatment discontinuation.
2) Assessed every 8 weeks from C1D1 up to the end of study.
3) Assessed every 12 weeks up to the end of study.
4) Assessed during the first 4 cycles of treatment.

1) Evaluadas desde el C1D1 hasta la discontinuación del tratamiento.
2) Evaluadas cada 8 semanas desde el C1D1 hasta el final del estudio.
3) Evaluadas cada 12 semanas hasta el final del estudio.
4) Evaluadas durante los primeros 4 ciclos de tratamiento.

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

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

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)

Yes

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

Yes

E.7.1.3.1

Other trial type description

Dose escalation of INC280 and cetuximab

Escalada de dosis del INC280 con cetuximab

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

E.8.1.1

Randomised

E.8.1.2

Open