Clinical Trials Register

Summary
EudraCT Number:	2011-005875-17
Sponsor's Protocol Code Number:	CMEK162X2110
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:	2012-03-06
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

2011-005875-17

A.3

Full title of the trial

A Phase Ib/II, multicenter, open-label, dose escalation study of LGX818 in combination with MEK162 in adult patients with BRAF V600 - dependent advanced solid tumors

Estudio fase Ib/II, multicéntrico, abierto, de escalado de dosis de LGX818 en combinación con MEK162, en pacientes adultos con tumores sólidos avanzados dependientes de BRAF V600

A.3.1

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

A Phase Ib/II study of LGX818 in combination with MEK162 in adult patients with BRAF dependent advanced solid tumors

Estudio fase Ib/II de LGX818 en combinación con MEK162 en pacientes adultos con tumores sólidos avanzados dependientes de BRAF

A.4.1

Sponsor's protocol code number

CMEK162X2110

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	Array Biopharma Inc
B.1.3.4	Country	United States
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	Array Biopharma Inc
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Array Biopharma Inc
B.5.2	Functional name of contact point	Margaret Vargo
B.5.3	Address:
B.5.3.1	Street Address	3200 Walmut Street
B.5.3.2	Town/ city	Boulder
B.5.3.3	Post code	CO80301
B.5.3.4	Country	United States
B.5.4	Telephone number	+13033861485
B.5.5	Fax number	+13033861252
B.5.6	E-mail	margie.vargo@arraybiopharma.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.3.2	Product code	LGX818
D.3.4	Pharmaceutical form	Capsule, hard
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	LGX818
D.3.9.2	Current sponsor code	LGX818
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.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.3.2	Product code	MEK162
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	MEK162
D.3.9.1	CAS number	606143-89-9
D.3.9.2	Current sponsor code	MEK162
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	15
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	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.3.2	Product code	LGX818
D.3.4	Pharmaceutical form	Capsule, hard
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	LGX818
D.3.9.2	Current sponsor code	LGX818
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	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: 4
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.3.2	Product code	LGX818
D.3.4	Pharmaceutical form	Capsule, hard
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	LGX818
D.3.9.2	Current sponsor code	LGX818
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: 5
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.3.2	Product code	LGX818
D.3.4	Pharmaceutical form	Capsule, hard
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	LGX818
D.3.9.2	Current sponsor code	LGX818
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: 6
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.3.2	Product code	LEE011
D.3.4	Pharmaceutical form	Capsule, hard
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	LEE011
D.3.9.3	Other descriptive name	LEE011
D.3.9.4	EV Substance Code	SUB31644
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	Yes
D.3.11.13.1	Other medicinal product type	LEE011 is an orallly bioavailable, small molecule inhibitor of CDK4/6. LEE011 exhibits highly especific inhibitory activity against CDK4/Cycline D1 and CDK6/Cycline D3 complexes.
D.IMP: 7
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.3.2	Product code	LEE011
D.3.4	Pharmaceutical form	Capsule, hard
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	LEE011
D.3.9.3	Other descriptive name	LEE011
D.3.9.4	EV Substance Code	SUB31644
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	Yes
D.3.11.13.1	Other medicinal product type	LEE011 in an orally bioavailable, small molecule inhibitor of CDK4/6. LEE011 exhibits hightly specific inhibitory activity against CDK4/Cycline D1 and CDK6/Cycline D3 complexes.

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

Patients with solid tumors harboring a BRAF V600 mutation.

Pacientes con tumores sólidos dependientes de mutación BRAF V600

E.1.1.1

Medical condition in easily understood language

Solid tumors

Tumores sólidos

E.1.1.2

Therapeutic area

Diseases [C] - Cancer [C04]

MedDRA Classification

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

Phase Ib: To estimate the MTD(s) and/or RP2D(s) of oral LGX818 in combination with oral MEK162 and of oral of LGX818 in combination with oral MEK162 and oral LEE011 in patients with BRAF V600-dependent advanced solid tumors.

Phase II: To assess clinical efficacy of the LGX818 and MEK162 dual combination and LGX818, MEK162 and LEE11 triple combination.

Fase I: Calcular la(s) DMT(s) y/o DRF2(s) de LGX818 oral en combinación con MEK162 oral y de LGX818 oral en combinación con MEK162 y LEE011 oral en pacientes con tumores sólidos avanzados dependientes de BRAF V600.

Fase II: Evaluar la eficacia clínica de la combinación doble de LGX818 y de MEK162 y de la triple combinación de LGX818, MEK162 y LEE011

E.2.2

Secondary objectives of the trial

1. Phase Ib and II : to characterize the safety and tolerability of LGX818 and MEK162 combination and LGX818, MEK162 and LEE011 combination.
2. Phase Ib : to determine the single and multiple dose PK profile of the LGX818 and MEK162 combination and LGX818, MEK162 and LEE011 combination.
3. Phase Ib : to assess preliminary anti-tumor activity of the LGX818 and MEK162 combination and the LGX818 and MEK162 and LEE011 combination.
4. Phase II : to further assess clinical efficacy of the LGX818 and MEK162 combination and the LGX818 and MEK162 and LEE011 combination.

1.Fase Ib y II: Caracterizar la seguridad y la tolerabilidad de LGX818 y de MEK162 en combinación y de la combinación de LGX818, MEK162 y LEE011 .
2.Fase Ib:Determinar el perfil PK de dosis única y múltiples de la combinación de LGX818 y MEK162 y de la combinación de LGX818, MEK162 y LEE011 .
3. Fase Ib: Evaluar la actividad antitumoral clínica preliminar de la combinación de LGX818 y MEK162 y de la combinación de LGX818, MEK162 y LEE011 .
4. Fase II: Evaluar mejor la eficacia clínica de la combinación de LGX818 y MEK162 y de la combinación de LGX818, MEK162 y LEE011.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

? Age ? 18 years for both phases and arms
? Histologically confirmed diagnosis of locally advanced or metastatic melanoma (stage IIIB to IV per American Joint Committee on Cancer [AJCC]), or confirmed diagnosis of non-resectable advanced metastatic colorectal cancer (mCRC), or any other indication upon agreement with the Sponsor, whose disease has progressed despite previous antineoplastic therapy or for whom no further effective standard therapy is available.
? Written documentation of BRAF V600E mutation, or any other BRAF V600 mutation.
? Evidence of measurable disease as determined by RECIST v1.1.
? World Health Organization (WHO) Performance Status ? 2.
? Negative serum pregnancy test within 72 hours prior to the first study
dose in all women of childbearing potential.
Other protocol-defined inclusion criteria may apply.

1.Edad ? 18 años para ambas Fases y grupos.
2. Diagnóstico histológicamente confirmado de melanoma metastásico o localmente avanzado (estadío IIIB a IV según el Comité Americano Conjunto sobre el Cáncer [AJCC]) o diagnóstico confirmado de cáncer colorrectal metastásico avanzado irresecable (CCRm) o cualquier otra indicación tras acuerdo con el investigador, cuya enfermedad haya progresado a pesar de la terapia antineoplásica previa y para los que no existan más terapias estándares eficaces.
3.Documentación por escrito de mutación BRAF V600E o cualquier otra mutación BRAF V600.
4.Evidencia de enfermedad medible determinada con los RECIST v1.1.
5.Estado funcional de la Organización Mundial de la Salud (OMS) ? 2.
6.Para todas las mujeres potencialmente fértiles, prueba de embarazo en suero negativa dentro de las 72 horas antes de la primera dosis del estudio.
Otros criterios de inclusión definidos por protocolo deben aplicar.

E.4

Principal exclusion criteria

? Progressive disease following prior treatment with RAF-inhibitors in combination with MEK-inhibitors.
? Symptomatic or untreated leptomeningeal disease.
? Symptomatic brain metastases. Patients are not permitted to receive enzyme inducing anti-epileptic drugs. For the triple combination, patients presenting any brain metastases are excluded.
? Known acute or chronic pancreatitis.
? History or current evidence of retinal disease, retinal vein occlusion or ophthalmopathy.
? Clinically significant cardiac disease.
? Patients with abnormal laboratory values at Screening/baseline. For the triple combination, patients with abnormal coagulation evaluations (INR/PT >1.5 x ULN or aPTT > 1.5 x ULN) are excluded.
? Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral LGX818/MEK162
? Previous or concurrent malignancy.
? Pregnant or nursing (lactating) women.
For addition of LEE011 in the triple combination, congenital long Qt syndrome or family history of unexpected sudden cardiac death and/or hypokalemia CTCAE Grade >=3.
Other protocol-defined exclusion criteria may apply.

1.Progresión de la enfermedad tras tratamiento previo con inhibidores de RAF en combinación con inhibidores de MEK.
2.Enfermedad sintomática o leptomeningea no tratada
3.Metástasis cerebrales sintomáticas. A los pacientes no se les permite recibir fármacos antiepilépticos inductores enzimáticos. Para los pacientes de la triple combinación: pacientes que presenten cualquier metástasis cerebral quedan excluidos
4.Pancreatitis crónica o aguda conocida.
5.Antecedentes o evidencia actual de enfermedad de la retina, oclusión venosa retiniana u oftalmopatía
6.Enfermedad cardíaca clínicamente significativa
7.Pacientes con valores anormales de laboratorio en la visita basal/de selección. Para la triple combinación, pacientes con valores anormales de coagulación (PT/ INR > 1.5 LSN o aPTT > 1.5 LSN) serán excluidos.
8.Deterioro de la función gastrointestinal (GI) o enfermedad GI que pueda alterar significativamente la absorción de LGX818/MEK162 oral
9.Enfermedad maligna previa o concurrente.
10.Mujeres embarazadas o en periodo de lactancia.
11.Para la adición de LEE011 en la combinación triple, síndrome de QT prolongado congénito o antecedentes familiares de muerte súbita cardíaca imprevista
Otros criterios de exclusión definidos por protocolo deben aplicar.

E.5 End points

E.5.1

Primary end point(s)

Phase Ib: Incidence of Dose Limiting Toxicities

Phase II : Disease control rate (DCR) as per RECIST v1.1 and Objective Response Rate (ORR) as per RECIST v1.1

Fase Ib: Incidencia de toxicidades limitantes de dosis

Fase II: Tasa de control de la enfermedad (TCE) según los RECIST v1.1 y Tasa de respuesta objetiva (TRO) según los RECIST v1.1

E.5.1.1

Timepoint(s) of evaluation of this end point

Phase Ib : up to 8 months

Phase II : up to 14 monts

Fase Ib: hasta 8 meses
Fase II: hasta 14 meses

E.5.2

Secondary end point(s)

1. Phase Ib and II : Incidence and severity of AE (as per CTCAE).
2. Phase Ib : plasma concentration at different timepoints prior and post study drug combination dosing on several days within Cycle 1 and subsequent cicles.
3. Phase Ib : ORR as per RECIST v1.1
4. Phase II : PFS as per RECIST 1.1

1. Fase Ib y II: Incidencia y severidad del AA (según CTCAE)
2. Fase Ib: Concentración plasmática frente a tiempo antes y después de la combinación del fármaco en estudio en distintos dias durante el ciclo 1 y ciclos posteriores
3. Fase Ib:TRO según los RECIST v1.1
4. Fase II: SLP según los RECIST v1.1 con la misma indicación

E.5.2.1

Timepoint(s) of evaluation of this end point

1. up to 17 months
2. up to 8 months
3. up to 8 months
4. up to 14 months

1. hasta 17 meses
2. hasta 8 meses
3. hasta 8 meses
4. Hasta 14 meses

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

dual/triple combination to determine MTD and/or RP2D followed by phase II to assess clinical eficac

Estudio escalado de dosis de LGX818 en combinación con MEK162 para calcular DMT(s) y/o DRF2(s)

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

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

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

E.8.2.3

Other

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

Belgium

Canada

France

Italy

Singapore

Spain

Switzerland

United States

E.8.7

Trial has a data monitoring committee

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 will be upon completion of the follow up period for the last patient treated with the LGX818 and MEK162 combination. This will be either upon SEC of the last patient treated or once the last patient in the Phase II part has died or all patients have completed SEC and have been followup for at least 18 months since the first dose of study treatment or have been lost to follow-up or withdrew consent, whichecer occurs first

El fin del estudio se producicrá tras completar el periodo de seguimiento el ultimo paciente tratado con la combinación de LGX818 y MEK162. Esto será tras la SEC del último paciente tratado o una vez el último paciente de la parte de la fase II haya muerto o todos los pacientes hayan completado la SEC y hayan sido controlados durante almenos 18 meses desde su primera dosis del tratamiento en estudio o se haya perdido el seguimiento o retirada del consentimiento, lo que ocurra antes.

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:

161

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

179

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)

Expected normal treatment of that condition

Tratamiento normal en esta condicion

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

2012-05-30

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2012-03-23

P. End of Trial
P.	End of Trial Status	Completed

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