Clinical Trials Register

Summary
EudraCT Number:	2016-002794-35
Sponsor's Protocol Code Number:	CPDR001F2301
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2016-12-14
Trial 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

2016-002794-35

A.3

Full title of the trial

A randomized, double-blind, placebo-controlled, phase III study comparing the combination of PDR001, dabrafenib and trametinib versus placebo, dabrafenib and trametinib in previously untreated patients with unresectable or metastatic BRAF V600 mutant melanoma

Estudio fase III, aleatorizado, doble ciego, controlado con placebo, que compara la combinación de PDR001, dabrafenib y trametinib frente a placebo, dabrafenib y trametinib, en pacientes con melanoma metastásico o irresecable con mutación BRAFV600 no tratados previamente

A.3.1

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

Study of safety and efficacy of PDR001 in combination with dabrafenib and trametinib in patients with a genetically distinct subtype of unresectable or metastatic melanoma, which is characterised by a mutation in the BRAF gene

Estudio de seguridad y eficacia de PDR001 en combinación con dabrafenib y trametinib en pacientes con melanoma avanzado

A.4.1

Sponsor's protocol code number

CPDR001F2301

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 Farmacéutica, S.A.
B.4.2	Country	Spain
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	34 90 0353036
B.5.5	Fax number	34 93 2479903
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	Yes
D.2.1.1.1	Trade name	Mekinist
D.2.1.1.2	Name of the Marketing Authorisation holder	Novartis Europharm Limited
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	Mekinist
D.3.2	Product code	TMT212
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	trametinib
D.3.9.1	CAS number	1187431-43-1
D.3.9.2	Current sponsor code	TMT212
D.3.9.3	Other descriptive name	TRAMETINIB DIMETHYL SULFOXIDE
D.3.9.4	EV Substance Code	SUB167251
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	2
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	Tafinlar
D.2.1.1.2	Name of the Marketing Authorisation holder	Novartis Europharm Limited
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	Tafinlar
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	dabrafenib
D.3.9.1	CAS number	1195768-06-9
D.3.9.2	Current sponsor code	DRB436
D.3.9.3	Other descriptive name	DABRAFENIB MESYLATE
D.3.9.4	EV Substance Code	SUB128623
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	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	PDR001
D.3.4	Pharmaceutical form	Powder for 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	not yet defined
D.3.9.2	Current sponsor code	PDR001
D.3.9.3	Other descriptive name	PDR001
D.3.9.4	EV Substance Code	SUB171710
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	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	Yes
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	Yes
D.2.1.1.1	Trade name	Mekinist
D.2.1.1.2	Name of the Marketing Authorisation holder	Novartis Europharm Limited
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	Mekinist
D.3.2	Product code	TMT212
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	trametinib
D.3.9.1	CAS number	1187431-43-1
D.3.9.2	Current sponsor code	TMT212
D.3.9.3	Other descriptive name	TRAMETINIB DIMETHYL SULFOXIDE
D.3.9.4	EV Substance Code	SUB167251
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	0.5
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	Yes
D.2.1.1.1	Trade name	Tafinlar
D.2.1.1.2	Name of the Marketing Authorisation holder	Novartis Europharm Limited
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	Tafinlar
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	dabrafenib
D.3.9.1	CAS number	1195768-06-9
D.3.9.2	Current sponsor code	DRB436
D.3.9.3	Other descriptive name	DABRAFENIB MESYLATE
D.3.9.4	EV Substance Code	SUB128623
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	75
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	Lyophilisate for solution for infusion
D.8.4	Route of administration of the placebo	Intravenous use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Unresectable or metastatic BRAF V600 mutant melanoma

melanoma metastásico e irresecable con mutación BRAF V600

E.1.1.1

Medical condition in easily understood language

Unresectable or metastatic melanoma, which is characterised by a mutation in the BRAF gene

melanoma metastásico o irresecable con mutación BRAF V600

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	19.0
E.1.2	Level	LLT
E.1.2	Classification code	10027481
E.1.2	Term	Metastatic melanoma
E.1.2	System Organ Class	100000004864

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

Part 1: Safety run-in
To determine the recommended regimen of PDR001 in combination with dabrafenib and trametinib for the randomized part (part 3)

Part 2: Biomarker cohort
To evaluate changes in the immune microenvironment and biomarker modulations upon treatment with PDR001 in combination with dabrafenib and trametinib

Part 3: Double-blind, randomized, placebo-controlled part
To compare the anti-tumor activity of PDR001 in combination with dabrafenib and trametinib versus placebo plus dabrafenib and trametinib as measured by PFS per investigator’s assessment according to RECIST 1.1

Parte 1: Pre-inclusión de seguridad
Para determinar el régimen recomendado de PDR001 en combinación con dabrafenib y trametinib para la parte aleatorizada (parte 3)
Parte 2: Cohorte de biomarcadores
Para evaluar los cambios en el microambiente inmunológico y la modulación de los biomarcadores tras el tratamiento con PDR001 en combinación con dabrafenib y trametinib.
Parte 3: Parte doble ciego, aleatorizada, controlada con placebo
Comparar la actividad antitumoral de PDR001 en combinación dabrafenib y trametinib frente a placebo más dabrafenib y trametinib, medida con la SLP según la evaluación del investigador, de acuerdo con los RECIST 1.1.

E.2.2

Secondary objectives of the trial

Part 1: Safety run-in
To determine safety and tolerability of PDR001 in combination with dabrafenib and trametinib
To evaluate preliminary anti-tumor activity of PDR001 in combination with dabrafenib and trametinib
To characterize pharmacokinetics (PK) of PDR001, dabrafenib and trametinib when administered in combination
To evaluate the prevalence and incidence of immunogenicity

Part 3: Double-blind, randomized, placebo-controlled part
To compare overall survival of PDR001 in combination with dabrafenib and trametinib versus placebo plus dabrafenib and trametinib
To compare the anti-tumor activity of PDR001 in combination with dabrafenib and trametinib versus placebo plus dabrafenib and trametinib as measured by ORR, DCR, DOR per investigator’s assessment according to RECIST 1.1
To evaluate safety and tolerability of PDR001 in combination with dabrafenib and trametinib versus placebo plus dabrafenib and trametinib

Parte 1: Pre-inclusión de seguridad
-Determinar la seguridad y tolerabilidad de PDR001 en combinación con dabrafenib y trametinib
-Evaluar la actividad antitumoral preliminar de PDR001 en combinación con dabrafenib y trametinib
-Caracterizar la farmacocinética (PK) de PDR001, dabrafenib y trametinib cuando se administran en combinación.
-Evaluar la prevalencia e incidencia de inmunogenicidad
Parte 3: Parte doble ciego, aleatorizada, controlada con placebo
-Comparar la supervivencia general de PDR001 en combinación dabrafenib y trametinib frente a placebo más dabrafenib y trametinib,.
-Comparar la actividad antitumoral de PDR001 en combinación
dabrafenib y trametinib frente a placebo más dabrafenib y trametinib, medida con la TRG, la TCE y la DR según la evaluación del investigador, de acuerdo con los RECIST 1.1.
-Evaluar la seguridad y tolerabilidad de PDR001 en combinación con dabrafenib y trametinib frente a placebo más dabrafenib y trametinib

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

• Histologically confirmed, unresectable or metastatic melanoma with BRAF V600 mutation
• Measurable disease according to RECIST 1.1
• ECOG performance status ≤ 1 (part 1: safety run-in), ≤ 2 (part 2: biomarker cohort and part 3: randomized part)
• Left ventricular ejection fraction (LVEF) ≥ lower limit of institutional normal (LLN)
• At least two cutaneous or subcutaneous lesions or nodal lesions for tumor sample collection (part 2: biomarker cohort )
• Adequate bone marrow and organ function

-Melanoma metastásico o irresecable, histológicamente confirmado con mutación BRAF V600
-Enfermedad medible según los RECIST 1.1
-Estado funcional del ECOG ≤ 1 (parte 1: pre inclusion de seguridad), ≤ 2 (parte 2: cohorte de biomarcadores y parte 3: aleatorizada)
-Fracción de eyección ventricular izquierda (FEVI) ≥ que el límite inferior de la normalidad (LIN)
-Al menos dos lesiones cutáneas o subcutáneas para la recogida de muestra de tumor (Parte 2: Cohorte de biomarcadores).
-Adecuado estado y funcionamiento de la médula ósea.

E.4

Principal exclusion criteria

• Any history of CNS metastases (part 1: safety run-in)
• Clinically active cerebral melanoma metastasis (part 2: biomarker cohort and part 3: randomized part)
• Subjects with uveal or mucosal melanoma
• Prior systemic anticancer therapy for unresectable or metastatic melanoma
• Neoadjuvant and/or adjuvant therapy for melanoma completed less than 6 months prior to enrollment
• Radiotherapy within 4 weeks prior to the first dose of study treatment
• Uncontrolled infections
• Active autoimmune disease, and/or history of autoimmune disease(s) that required treatment
• Known history of prior or current retinal vein occlusion (RVO)

-Cualquier antecedente de metástasis del SNC (parte 1: Pre inclusion de seguridad)
-Metástasis cerebrales de melanoma clínicamente activas (parte 2: cohorte de biomarcadores y parte 3: aleatorizada).
-Pacientes con melanoma uveal o de la mucosa
-Terapia antineoplásica sistémica previa para el melanoma metastásico o irresecable
-Terapia neoadyuvante y/o adyuvante para el melanoma, finalizada menos de 6 meses antes de la inclusión
-Radioterapia dentro de las 4 semanas antes de la primera dosis del tratamiento del studio
- Infecciones no controladas.
-Enfermedad autoimmune activa y/o antecedentes de enfermedad(es) autoimmune(s) que precisen tratamiento
-Historia previa o actual de oclusión venosa de la retina (OVR)

E.5 End points

E.5.1

Primary end point(s)

Part 1: Safety run-in
• Incidence of DLTs during the first 8 weeks of treatment for each dose level associated with administration of PDR001 in combination of dabrafenib and trametinib.

Part 2: Biomarker cohort
• Descriptive statistics of biomarker values and changes from baseline by visit

Part 3: Double-blind, randomized, placebo-controlled part
• Investigator assessed PFS according to RECIST 1.1

Parte 1: Preinclusión de seguridad
La variable principal es la incidencia de toxicidades limitantes de dosis (DLTs) durante las primeras 8 semanas (56 días) de PDR001 en combinación con dabrafenib y trametinib.
Parte 2: Cohorte de biomarcadores
Se resumirán estadísticas descriptivas de valores de microambiente
inmunológico y de modulación del biomarcador y cambios, respecto a los valores basales, por visita y grupo de tratamiento.
Parte 3 : Parte doble ciego, aleatorizada, controlada con placebo
Medida de la SLP según la evaluación del investigador, de acuerdo con los RECIST 1.1.

E.5.1.1

Timepoint(s) of evaluation of this end point

Part 1 Safety Run-in
Every study visit and safety FU on days 30, 60, 90, 120 and 150

Part 2: Biomarker cohort
Baseline, Day 1 Cycle 1, Day 15 Cycle 1, Cycle 3 and at disease progression study visit and safety FU on days 30, 60, 90, 120 and 150

Part 3: Double-blind, randomized, placebo-controlled part
C4D1 (± 7 days), every 8 weeks, then from C22D1 (± 7 days), every 12 weeks thereafter

Parte 1 Pre-inclusión de seguridad
Cada visita del estudio y visitas de seguimiento de seguridad en los días: 30,60,90,120 y 150
Parte 2 Cohorte de biomarcadores
Visita basal, Día 1 Ciclo 1, Día 15 Ciclo 1, ciclo 3 y en las visitas del estudio de progresión de la enfermedad y seguimiento de seguridad en los días 30,60,90,120 y 150
Parte 3 : Parte doble ciego, aleatorizada, controlada con placebo
C4D1 (± 7 días), cada 8 semanas, entonces desde C22D1 (± 7 días ), a partir de ahí , cada 12 semanas.

E.5.2

Secondary end point(s)

Part 1: Safety run-in
1) Safety and tolerability: Incidence and severity of AEs and SAEs, including changes in laboratory values, ECOG PS, vital signs, liver and cardiac parameters, Dose interruptions, reductions, and dose intensity
2) OS PFS, ORR, DOR, DCR by investigator’s assessment according to RECIST 1.1
please refer to protocol for other secondary endpoints

Part 3: Double-blind, randomized, placebo-controlled part
1) OS (key secondary), ORR, DOR and DCR by investigator’s assessment according to RECIST 1.1
2) Safety and tolerability: Incidence and severity of AEs and SAEs, including changes in laboratory values, ECOG PS, vital signs, liver and cardiac parameters, dose interruptions, reductions, and dose intensity
3) Change from baseline in EORTC QLQ-C30, EQ-5D, and FACT-M melanoma subscale
please refer to protocol for other secondary endpoints

Parte 1 Pre-inclusión de seguridad
-Seguridad y tolerabilidad : Indicencia y severidad de los acontecimientos adversos (AEs) y SAEs, incluyendo los cambios en los valores de laboratorio, ECOG PS , signos vitales, hepáticos y parámetros cardíacos. Interrupciones de dosis, reducciones e intensidad de dosis.
- OS PFS, ORR, DOR, DCR según la evaluación del investigador, de acuerdo con los RECIST 1.1.
Refiérase al protocolo para otros objetivos secundarios.

Parte 3 : Parte doble ciego, aleatorizada, controlada con placebo
- OS (objetivos principales) , ORR, DOR, DCR según la evaluación del investigador, de acuerdo con los RECIST 1.1.
- Seguridad y tolerabilidad: Incidencia y severidad de los acontecimientos adversos (AEs) y SAEs, incluyendo los cambios en los valores de laboratorio, ECOG PS , signos vitales, evaluaciones hepáticas y cardíacas .Interrupciones de dosis, reducciones e intensidad de dosis.
- Cambios desde la visita basal de los cuestionarios EuroQoL (EQ-5D) y de calidad de vida de la Organización Europea para la investigación y el tratamiento del cáncer (QLQ-C30 de la EORTC) y sub-escala de melanoma de FACT-M
Refiérase al protocolo para otros objetivos secundarios.

E.5.2.1

Timepoint(s) of evaluation of this end point

Part 1 Safety Run-in
1) Every study visit and safety FU on days 30, 60, 90, 120 and 150
2) at Cycle 4 Day 1 (± 7 days), then every 8 weeks, until Cycle 22 Day 1 (± 7 days) when frequency will switch to every 12 weeks

Part 3: Double-blind, randomized, placebo-controlled part
1) at Cycle 4 Day 1 (± 7 days), then every 8 weeks, until Cycle 22 Day 1 (± 7 days) when frequency will switch to every 12 weeks and Survival FU until Death or lost to FU
2) Every study visit and safety FU on days 30, 60, 90, 120 and 150
3) Baseline, Cycle 3 Day 1, every 8 weeks for the first 12 cycles and every 12 weeks thereafter until confirmed PD, 30 days post PD and 60 days post PD

Parte 1 Pre-inclusión de seguridad
1) Cada visita del estudio y seguimiento de seguridad en los días: 30,60,90,120 y 150
2) En el ciclo 4 día 1 (± 7), desde entonces cada 8 semanas, hasta el ciclo 22 día 1 (± 7) cuando la frecuencia cambiará a cada 12 semanas.
Parte 3 : Parte doble ciego, aleatorizada, controlada con placebo
1) En el ciclo 4 día 1 (± 7), desde entonces cada 8 semanas, hasta el ciclo 22 día 1 (± 7) cuando la frecuencia cambiará a cada 12 semanas y seguimiento de supervivencia hasta muerte o pérdida de seguimiento.
2) Cada visita del estudio y seguimiento de seguridad en los días: 30,60,90,120 y 150
3) Visita Basal, Ciclo 3 Día 1, cada 8 semanas para el primero de los 12 ciclos y cada 12 semanas, a partir de ahi, hasta confirmado PD, 30 días post PD y 60 días port PD

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

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

Yes

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)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

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)

Yes

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

140

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

Colombia

Denmark

France

Greece

Hungary

Italy

Japan

Korea, Republic of

Mexico

Netherlands

Poland

Russian Federation

Spain

Taiwan

Thailand

Turkey

United Kingdom

United States

E.8.7

Trial has a data monitoring committee

Yes

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

The study will end once the final OS analysis is performed approximately when 197 deaths are observed or when statistical significance is reached for OS analysis, (see Section 10) and the final analysis of study data is conducted. All available data from all patients up to this cutoff data will be analyzed. If the primary analysis of PFS does not demonstrate treatment benefit, the follow-up for OS will end.

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:

409

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

129

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

302

F.4.2.2

In the whole clinical trial

538

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)

At the end of the study, every effort will be made to continue provision of investigational treatment outside this study through an alternative setting to subjects who in the opinion of the investigator are still deriving clinical benefit.
If the primary analysis of PFS does not demonstrate treatment benefit, the follow-up for OS will end.

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

2017-02-07

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2017-02-01

P. End of Trial
P.	End of Trial Status	Ongoing

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