Clinical Trials Register

Summary
EudraCT Number:	2012-004551-36
Sponsor's Protocol Code Number:	CLEE011X2105
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2013-08-08
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

2012-004551-36

A.3

Full title of the trial

A phase Ib/II, multicenter, study of LEE011 in combination with LGX818 in adult patients with BRAF mutant melanoma

Estudio fase Ib/II, multicéntrico, de LEE011 en combinación con LGX818, en pacientes adultos con melanoma con mutación BRAF

A.3.1

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

Safety and efficacy study of LEE011 and LGX818 in patients with BRAF mutant melanoma

Estudio de seguridad y eficacia en pacientes adultos con melanoma con tumores con mutación BRAF

A.4.1

Sponsor's protocol code number

CLEE011X2105

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 Oncoogía (GMO)
B.5.3	Address:
B.5.3.1	Street Address	Gran Via 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.3.2	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.3.9.1	CAS number	LEE011
D.3.9.2	Current sponsor code	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	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	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.3.9.1	CAS number	LGX818
D.3.9.2	Current sponsor code	LGX818
D.3.9.3	Other descriptive name	LGX818
D.3.9.4	EV Substance Code	SUB32790
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: 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	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.3.9.1	CAS number	LEE011
D.3.9.2	Current sponsor code	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	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	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.3.9.1	CAS number	LEE011
D.3.9.2	Current sponsor code	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	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.3.9.1	CAS number	LGX818
D.3.9.2	Current sponsor code	LGX818
D.3.9.3	Other descriptive name	LGX818
D.3.9.4	EV Substance Code	SUB32790
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: 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	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.3.9.1	CAS number	LGX818
D.3.9.2	Current sponsor code	LGX818
D.3.9.3	Other descriptive name	LGX818
D.3.9.4	EV Substance Code	SUB32790
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: 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	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.3.9.1	CAS number	LGX818
D.3.9.2	Current sponsor code	LGX818
D.3.9.3	Other descriptive name	LGX818
D.3.9.4	EV Substance Code	SUB32790
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.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

locally advanced or metastatic BRAF mutant melanoma

melanoma metastásico o localmente avanzado con mutación BRAF

E.1.1.1

Medical condition in easily understood language

melanoma

E.1.1.2

Therapeutic area

Diseases [C] - Cancer [C04]

MedDRA Classification

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

Phase Ib: To estimate the MTD(s) and/or determine
the RP2D of oral LEE011 in combination with oral
LGX818 in patients with BRAF mutant melanoma.
Phase II:
Part 1: To assess the anti-tumor activity of LEE011 in
combination with LGX818 vs. LGX818 alone in
patients with metastatic BRAF mutant melanoma who are naïve to prior selective BRAFi treatment
Part 2: To assess the anti-tumor activity of LEE011 in
combination with LGX818 in patients with metastatic
BRAF mutant melanoma who are resistant to prior
selective BRAFi treatment

Fase Ib: Calcular la(s) DMT(s) y/o DRF2 de LEE011 oral en combinación con LGX8181 oral en pacientes con melanoma con mutación BRAF.

Fase II:
Parte 1: Evaluar la actividad antitumoral de LEE011 en combinación con LGX818 frente a LGX818 en monoterapia en pacientes con melanoma metastásico con mutación BRAF que son naïves (no han recibido tratamiento previo) al tratamiento con inhibidor selectivo de BRAF.

Parte 2: Evaluar la actividad antitumoral de LEE011 en combinación con LGX818 en pacientes con melanoma metastásico con mutación BRAF que sean resistentes al tratamiento con inhibidor selectivo de BRAF.

E.2.2

Secondary objectives of the trial

- To characterize the safety and tolerability of LEE011 in combination with LGX818.
- To characterize the PK profiles of LEE011 and LGX818 as well as evaluate any other clinically significant metabolites that may be identified.
- To assess preliminary clinical anti-tumor activity of the LEE011 and LGX818 combination.

Fase Ib + II: Caracterizar la seguridad y tolerabilidad de LEE011 en combinación con LGX818.
Fase Ib + II: Caracterizar los perfiles PK de LEE011 y LGX818 además de evaluar cualquier otro metabolito clínicamente significativo que pueda ser identificado.
Evaluar la actividad antitumoral clínica preliminar de la combinación de LEE011 y LGX818

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

- Age >18 years.
- Diagnosis of locally advanced or metastatic melanoma along with written documentation of BRAF V600 mutation.
- ECOG performance status of 0 ? 2.
- Patients enrolled into Phase Ib must have evidence of evaluable and/or measurable disease as determined by RECIST v1.1.
- Patients enrolled into Phase II (BRAFi naïve and resistant) must have evidence of measurable
disease as determined by RECIST v1.1.
- Archival tumor tissue must be obtained for patients enrolled in Phase Ib and Phase II arm 1a/b- BRAFi naïve patients. If an archival tumor tissue is
not available, a fresh tumor sample is acceptable.
- For patients enrolled in the phase II arm 2, patients must agree to undergo a fresh tumor biopsy unless one was collected prior to study entry
but at the time of disease relapse from the most recent BRAFi treatment.
Other, protocol related inclusion criteria may apply.

1. Edad ?18 años.
2. Diagnóstico histológicamente confirmado de melanoma metastásico o localmente avanzado junto con documentación por escrito de mutación BRAF V600.
3. Estado funcional del Grupo de Oncología Cooperativo del este (ECOG) de 0-2.
4. Los pacientes incluidos en la fase Ib deberán presentar evidencia de enfermedad evaluable y/o medible, determinado con los RECIST v.1.1.
5. Los pacientes incluidos en la fase II (resistentes y naïve a BRAFi) deberán presentar evidencia de enfermedad medible determinada con los RECIST v.1.1.
6. Una muestra de tumor representativa disponible para análisis molecular, excepto en el caso de que Novartis y el Investigador acuerden lo contrario
- El tejido de tumor almacenado deberá obtenerse de los pacientes naïve a BRAFi incluidos en el grupo 1a/b de la fase Ib y de la fase II. Si no se dispone de tejido de tumor almacenado, se acepta una muestra de tumor fresco.
- Los pacientes incluidos en el grupo 2 de la fase II (resistentes a BRAFi) deberán acceder a que se les realice una biopsia de tumor fresco, a menos que ya se haya recogido una antes de entrar en el estudio pero en el momento de la recaída de la enfermedad del tratamiento con BRAFi más reciente.
7. Deberá haber transcurrido un intervalo suficiente entre la última dosis de la terapia antineoplásica previa (incluyendo terapias citotóxicas y biológicas) y la inclusión en este estudio para permitir que hayan disminuido los efectos de la terapia previa:
(a) Quimioterapia citotóxica: un mínimo de 2 semanas para toda la quimioterapia citotóxica previa (6 semanas para nitrosureas o mitomicina-C).
(b) Terapia biológica (por ejemplo, anticuerpos): ? 4 semanas.

E.4

Principal exclusion criteria

- Symptomatic brain metastases.
- Symptomatic or untreated leptomeningeal disease.
- Patients with inadequate laboratory values during screening.
- In the phase II BRAFi naïve arms (1a/b), prior exposure to CDK4/6 inhibitor (e.g., PD 0332991)
- Impaired cardiac function or clinically significant cardiac diseases.
- Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of LEE011 or LGX818.
- Patients with concurrent severe and/or uncontrolled concurrent medical conditions.
- Previous or concurrent malignancy.
- Major surgery < 2 weeks before starting study treatment
- Known diagnosis of human immunodeficiency virus (HIV) or hepatitis

1. Metástasis cerebrales sintomáticas.
2. Enfermedad leptomeníngea no tratada o sintomática.
3. Pacientes con los siguientes valores de laboratorio durante la selección:
- Recuento absoluto de neutrófilos (RAN) ? 1,500/mm3 [1.5 x 109/L]
- Hemoglobina (Hgb) ? 9 g/dL,
- Plaquetas ? 75,000/mm3 [75 x 109/L]
- Creatinina sérica ? 1.5 x LSN
- Bilirrubina total sérica ? 1.5 x límite superior de normalidad (LSN)
- AST/SGOT y ALT/SGPT ? 3 x LSN o AST y ALT ? 5 x LSN, en presencia de metástasis hepáticas.
4. En los grupos de pacientes naïve a BRAFi de la fase II (1a/b), exposición previa a inhibidor CDK4/6 (por ejemplo, PD 0332991)
5. Deterioro de la función cardiaca o enfermedad cardíaca clínicamente significativa, incluyendo algo de lo siguiente:
- Fracción de eyección ventricular izquierda (LVEF) ? 45% determinada con ventriculografía isotópica (MUGA) o ecocardiograma (ECHO). Por favor recuerde: los pacientes con LVEF por debajo del límite inferior de normalidad del centro serán excluidos del estudio.
- Síndrome de QT prolongado congénito o antecedentes familiares de muerte súbita cardíaca.
- QT corregido con Fredericia (QTcF) >450 ms para varones y >470 ms para mujeres en el ECG de selección

E.5 End points

E.5.1

Primary end point(s)

1. Incidence of Dose Limiting Toxicities (Phase Ib)
2. Progression Free Survival (PFS) - Phase II
3. Objective Response Rate (ORR) - Phase II

Fase Ib:
Incidencia de toxicidades limitantes de dosis (TLDs) en el ciclo 1
Fase II:
Brazos 1a/b: Supervivencia libre de progresión (SLP) según los RECIST v1.1
Brazo 2: Tasa de respuesta objetiva (TRO) según los RECIST v1.1

E.5.1.1

Timepoint(s) of evaluation of this end point

1. cycle 1 = 28 days
2-3. 23 months after FPFV

1. Ciclo 1 = 28 dias
2-3. 23 meses después de la primera visita del primer paciente

E.5.2

Secondary end point(s)

1. Number of Adverse Events
2. Number of Serious Adverse Events
3. Plasma concentration-time profiles
4. Overall Response Rate (ORR)
5. Progression Free Survival (PFS)
6. Duration Of Response (DOR)
7. Overall Survival (OS)

Acontecimientos adversos (AAs), AAs graves (AAGs), cambios en los valores bioquímicos y hematológicos, constantes vitales, electrocardiogramas (ECGs), interrupciones de dosis, reducciones e intensidad de dosis.
Perfiles de concentración-tiempo en plasma de LEE011 y de LGX818, parámetros PK, incluyendo pero no limitado a el AUCtau, la Cmin, la Cmax, la Tmax, la proporción de acumulación (Racc)
Respuesta del tumor según los RECIST v1.1: tasa de respuesta global (TRG) (fase Ib y brazos 1a/1b de la fase II), supervivencia libre de progresión (SLP) (fase Ib y brazo 2 de las fase II), duración de la respuesta (DR) (fase Ib, brazos 1a/1b/2 de la fase II) y supervivencia global (SG) (brazo 1a/1b/2 de la fase II)

E.5.2.1

Timepoint(s) of evaluation of this end point

1-2 and 4-7. approx. 23 months
3. 28 days

1-2 y 4-7: aproximadamente 23 meses
3. 28 días

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

Yes

E.6.13.1

Other scope of the trial description

Dose escalation study of LEE011 LGX818 combined with DMT to calculate (s) and / or DRF2 (s)

Estudio de escalado de dosis de LEE011 en combinación con LGX818 para calcular DMT(s) y/o DRF2(s)

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 combination to determine MTD and/or RP2D of the combination of LEE011+ LGX818

escalado de dosis de LGX818 en combinación con LEE011 para calcular la DMT/DR

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

Yes

E.8.1.2

Open

Yes

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.8.2.4

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

Canada

France

Italy

Netherlands

Argentina

Australia

Brazil

Germany

Spain

United Kingdom

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

Phase Ib and II of the study will end when the treatment period, safety follow-up, disease follow-up and survival follow-up (only for phase II) have ended for all patients or when the study is terminated early.

La fase Ib y II del estudio finalizará cuando haya finalizado el periodo de tratamiento, el seguimiento de seguridad, el seguimiento de la enfermedad y el seguimiento de la supervivencia (sólo para la fase II) para todos los pacientes, como se ha descrito en el Apartado 7.1.5 o cuando el estudio finalice prematuramente

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:

100

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

150

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)

none. follow up visits every 3 months (survival follow up)

Ninguno. Visitas de seguimiento cada 3 meses (supervivencia de seguimiento)

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

2013-11-11

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2013-10-09

P. End of Trial
P.	End of Trial Status	Prematurely Ended
P.	Date of the global end of the trial	2015-04-13

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