Clinical Trials Register

Summary
EudraCT Number:	2016-000588-17
Sponsor's Protocol Code Number:	MK-3475-426
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:	2016-08-05
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

2016-000588-17

A.3

Full title of the trial

A Phase III Randomized, Open-label Study to Evaluate Efficacy and Safety of Pembrolizumab (MK-3475) in Combination with Axitinib versus Sunitinib Monotherapy as a First-line Treatment for Locally Advanced or Metastatic Renal Cell Carcinoma (mRCC) (KEYNOTE-426)

Estudio de fase III, aleatorizado y abierto para evaluar la eficacia y la seguridad de pembrolizumab (MK-3475) en combinación con axitinib frente a sunitinib en monoterapia como tratamiento de primera línea del carcinoma renal metastásico (CRm) o localmente avanzado (KEYNOTE-426)

A.3.1

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

A clinical study of Pembrolizumab plus axitinib vs. sunitinib in advanced kidney cancer

Un estudio Clinico pembrolizumab más axitinib frente a sunitinib en monoterapia en el carcinoma renal avanzado

A.3.2

Name or abbreviated title of the trial where available

Pembrolizumab plus axitinib vs. sunitinib monotherapy in advanced/metastatic renal cell carcinoma

Pembrolizumab más axitinib frente a la monoterapia con sunitinib en el carcinoma avanzado / metastás

A.4.1

Sponsor's protocol code number

MK-3475-426

A.5.4

Other Identifiers

Name:

KEYNOTE

Number:

426

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	Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., 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	Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., 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	Merck Sharp & Dohme de España S.A.
B.5.2	Functional name of contact point	Investigación Clínica
B.5.3	Address:
B.5.3.1	Street Address	C/ Josefa Valcárcel, 38
B.5.3.2	Town/ city	Madrid
B.5.3.3	Post code	28027
B.5.3.4	Country	Spain
B.5.4	Telephone number	+34913210600
B.5.5	Fax number	+34913210590
B.5.6	E-mail	ensayos_clinicos@merck.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	Keytruda
D.2.1.1.2	Name of the Marketing Authorisation holder	Merck Sharp and Dohme, Ltd
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	pembrolizumab
D.3.2	Product code	MK-3475; SCH900475
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	pembrolizumab
D.3.9.1	CAS number	1374853-91-4
D.3.9.2	Current sponsor code	MK-3475
D.3.9.3	Other descriptive name	Anti-PD-1 monoclonal antibody
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	25
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)	Yes
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: 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	INLYTA (axitinib)
D.2.1.1.2	Name of the Marketing Authorisation holder	PF PRISM C.V., an indirect, wholly-owned affiliate of Pfizer Inc.
D.2.1.2	Country which granted the Marketing Authorisation	United States
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	Axitinib
D.3.4	Pharmaceutical form	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	axitinib
D.3.9.1	CAS number	319460-85-0
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	1
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	INLYTA (axitinib)
D.2.1.1.2	Name of the Marketing Authorisation holder	PF PRISM C.V., an indirect, wholly-owned affiliate of Pfizer Inc.
D.2.1.2	Country which granted the Marketing Authorisation	United States
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	Axitinib
D.3.4	Pharmaceutical form	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	axitinib
D.3.9.1	CAS number	319460-85-0
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	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: 4
D.1.2 and D.1.3	IMP Role	Comparator
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	SUTENT (sunitinib malate)
D.2.1.1.2	Name of the Marketing Authorisation holder	C.P. Pharmaceuticals International C.V, a wholly owned subsidiary of Pfizer Inc
D.2.1.2	Country which granted the Marketing Authorisation	United States
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	sunitinib
D.3.4	Pharmaceutical form	Capsule
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	sunitinib
D.3.9.1	CAS number	341031-54-7
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	12.5
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	Comparator
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	SUTENT (sunitinib malate)
D.2.1.1.2	Name of the Marketing Authorisation holder	C.P. Pharmaceuticals International C.V, a wholly owned subsidiary of Pfizer Inc
D.2.1.2	Country which granted the Marketing Authorisation	United States
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	sunitinib
D.3.4	Pharmaceutical form	Capsule
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	sunitinib
D.3.9.1	CAS number	341031-54-7
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.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

Advanced Kidney Cancer

Cancer renal avanzado

E.1.1.1

Medical condition in easily understood language

Advanced Kidney Cancer

Cancer renal avanzado

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	10023400
E.1.2	Term	Kidney cancer
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

1. To evaluate and compare PFS per RECIST 1.1 as assessed by BICR in subjects. treated with pembrolizumab plus axitinib versus sunitinib monotherapy.
2. To evaluate and compare OS in subjects treated with pembrolizumab plus axitinib versus sunitinib monotherapy.

1. Evaluar y comparar la SSP conforme a los criterios RECIST 1.1, evaluada mediante una RCIE, en sujetos tratados con pembrolizumab más axitinib en comparación con sunitinib en monoterapia.
2. Evaluar y comparar la SG en sujetos tratados con pembrolizumab más axitinib en comparación con sunitinib en monoterapia.

E.2.2

Secondary objectives of the trial

1. To compare ORR and DCR per RECIST 1.1 as assessed by BICR in subjects treated with a combination of pembrolizumab plus axitinib versus sunitinib monotherapy. DOR will also be evaluated.
2. To evaluate and compare safety and tolerability profiles in subjects treated with pembrolizumab plus axitinib versus sunitinib monotherapy.
3. To compare time to deterioration (TTD) based on the Functional Assessment of Cancer Therapy Kidney Symptom Index—Disease-Related Symptoms (FKSI-DRS) scale in subjects treated with pembrolizumab plus axitinib versus sunitinib monotherapy.
4. To assess the longitudinal score changes from baseline to 42 weeks as measured by European Organization for the Research and Treatment of Cancer (EORTC) QLQ-C30 global health status/quality of life scale.

1. Comparar la TRO y TCE conforme a los criterios RECIST 1.1, evaluadas mediante una RCIE, en sujetos tratados con pembrolizumab más axitinib en comparación con sunitinib en monoterapia. También se evaluará la DR.
2. Evaluar y comparar los perfiles de seguridad y tolerabilidad en sujetos tratados con pembrolizumab más axitinib en comparación con sunitinib en monoterapia.
3. Comparar el tiempo transcurrido hasta el deterioro (TTHD) según la escala FKSI-DRS (Índice de síntomas renales de la Evaluación funcional del tratamiento del cáncer–Síntomas relacionados con la enfermedad) en sujetos tratados con pembrolizumab más axitinib en comparación con sunitinib en monoterapia.
4. Evaluar las variaciones de puntuación longitudinales entre el período basal y la semana 42 medidas mediante la escala de estado de salud general/calidad de vida del cuestionario QLQ-C30 de la Organización Europea para la Investigación y el Tratamiento del Cáncer (EORTC).

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

Merck will conduct Future Biomedical Research on DNA (blood and tissue) specimens collected during this clinical trial. Such research is for biomarker testing to address emergent questions not described elsewhere in the protocol (as part of the main trial) and will only be conducted on specimens from appropriately consented subjects. The objective of collecting specimens for Future Biomedical Research is to explore and identify biomarkers that inform the scientific understanding of diseases and/or their therapeutic treatments. The overarching goal is to use such information to develop safer, more effective drugs, and/or to ensure that subjects receive the correct dose of the correct drug at the correct time.

El promotor realizará investigaciones biomédicas futuras con las muestras obtenidas para tal finalidad durante este ensayo clínico. Dichas investigaciones podrán incluir análisis genéticos (ADN), determinación de perfiles de expresión génica (ARN), proteómica, metabolómica (suero, plasma) y/o determinación de otros analitos.
Estas investigaciones tendrán por objeto el análisis de biomarcadores con el fin de abordar aspectos nuevos que no se describen en otras partes del protocolo (como parte del ensayo principal) y solo se llevarán a cabo en muestras de los sujetos que hayan otorgado el consentimiento correspondiente. El objetivo de la obtención de muestras para investigaciones biomédicas futuras consiste en estudiar e identificar biomarcadores que proporcionen información a los científicos sobre las enfermedades y/o sus tratamientos. El objetivo último consiste en utilizar tal información para desarrollar vacunas y fármacos más seguros y eficaces o para garantizar que los sujetos reciban la dosis correcta del fármaco o vacuna adecuado en el momento preciso.

E.3

Principal inclusion criteria

- Be > or = 18 years of age on day of signing informed consent
- Have histologically confirmed diagnosis of RCC with clear cell component with or without sarcomatoid features
- Have locally advanced/metastatic disease (i.e., Stage IV RCC per American Joint Committee on Cancer) or have recurrent disease
- Have measurable disease per RECIST 1.1 as assessed by the investigator /site radiologist. Target lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions
- Have received no prior systemic therapy for advanced RCC
- Provide tumor tissue for biomarker analysis
- Demonstrate adequate organ function

- Tener una edad mínima de 18 años el día de firma del consentimiento informado.
- Tener un diagnóstico confirmado histológicamente de CR con un componente de células claras, con o sin características sarcomatoideas.
- Presentar enfermedad localmente avanzada/metastásica (es decir, CR en estadio IV según el American Joint Committee on Cancer) o enfermedad recurrente.
- Presentar enfermedad mensurable conforme a los criterios RECIST 1.1, según la evaluación del investigador o radiólogo del centro. Las lesiones diana ubicadas en una zona previamente irradiada se considerarán mensurables siempre que se haya constatado progresión en dichas lesiones.
- No haber recibido ningún tratamiento sistémico previo para el CR avanzado.
- Proporcionar el tejido tumoral para el análisis de biomarcadores
- Presentar una función orgánica adecuada

E.4

Principal exclusion criteria

- Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to randomization
- Has had major surgery within 4 weeks prior to randomization or radiation therapy within 2 weeks prior to randomization, or who has not recovered (i.e., < or = Grade 1 or at baseline) from AEs due to prior treatment
- Has had prior treatment with any anti-PD-1, or PD-L1, or PD-L2 agent or an antibody targeting any other immune-regulatory receptors or mechanisms. Examples of such antibodies include (but are not limited to) antibodies against IDO, PD-L1, IL-2R, and GITR
- Has received prior therapy with VEGF/VEGFR or mTOR targeting agents
- Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to randomization
- Has an active autoimmune disease requiring systemic treatment within the past 3 months or a documented history of clinically severe autoimmune disease, or a syndrome that requires systemic or immunosuppressive agents
- Has a known additional malignancy that has progressed or has required active treatment in the last 3 years
- Has known active CNS metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are stable
- Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis
- Has a clinically significant gastrointestinal (GI) abnormality including: Inability to take oral medication, Requirement for IV alimentation, Prior surgical procedures affecting absorption including total gastric resection, Treatment for active peptic ulcer within the past 6 months, Active GI bleeding, as evidenced by hematemesis, hematochezia or melena in the past 3 months without evidence of resolution documented by endoscopy or colonoscopy, Intraluminal metastatic lesion with suspected bleeding, inflammatory bowel disease, ulcerative colitis or other GI condition associated with increased risk of perforation, or history of GI perforation, Malabsorption syndromes, Inflammatory bowel disease
- Has QT interval corrected for heart rate (QTc) > or = 480 msec
- Has a history of any of the following cardiovascular conditions within 12 months of screening: Myocardial infarction, Unstable angina pectoris, Cardiac angioplasty or stenting, Coronary/peripheral artery bypass graft, Class III or IV congestive heart failure per New York Heart Association, Cerebrovascular accident or transient ischemic attack
- Has a history of deep vein thrombosis or pulmonary embolism within 6 months of screening
- Has poorly controlled hypertension defined as systolic blood pressure (SBP) > or = 150 mm Hg and/or diastolic blood pressure (DBP) > or = 90 mm Hg
- Has evidence of inadequate wound healing
- Has active bleeding disorder or other history of significant bleeding episodes within 30 days of randomization
- Has hemoptysis within 6 weeks prior to randomization
- Has current use or anticipated need for treatment with drugs or foods that are known strong cytochrome P450 (CYP3A4/5) inhibitors
- Has current use or anticipated need for treatment with drugs that are known strong CYP3A4/5 inducers
- Has had a prior solid organ transplant

- Está participando o ha participado en un estudio de un fármaco o dispositivo en investigación en las cuatro semanas previas a la aleatorización.
- Se ha sometido a una intervención de cirugía mayor en las cuatro semanas previas a la aleatorización o a radioterapia en las dos semanas previas a la aleatorización o bien no se ha recuperado (es decir, recuperación a un grado ≤ 1 o la situación basal) de los AA debidos al tratamiento previo.
- Ha recibido tratamiento previo con algún otro fármaco anti-PD-1, anti-PD-L1 o anti-PD-L2 o con un anticuerpo dirigido contra otros mecanismos o receptores inmunorreguladores. Ejemplos de anticuerpos de este tipo son, entre otros, anticuerpos contra IDO, PD-L1, IL-2R y GITR.
- Ha recibido tratamiento previo con fármacos dirigidos contra VEGF/VEGFR o mTOR.
- Tiene un diagnóstico de inmunodeficiencia o ha recibido esteroides sistémicos o alguna otra forma de tratamiento inmunodepresor en los siete días previos a la aleatorización.
- Padece una enfermedad autoinmunitaria activa con necesidad de tratamiento sistémico en los tres últimos meses o tiene antecedentes documentados de una enfermedad autoinmunitaria clínicamente grave o de un síndrome que requiera tratamiento sistémico o inmunodepresor.
- Presenta otra neoplasia maligna conocida que está en progresión o ha necesitado tratamiento activo en los tres últimos años.
- Presenta metástasis activas conocidas en el SNC y/o meningitis carcinomatosa. Los sujetos con metástasis cerebrales tratadas anteriormente podrán participar siempre que se encuentren estables.
- Tiene antecedentes de neumonitis (no infecciosa) que precisó esteroides o una neumonitis activa.
- Presenta un anomalía digestiva clínicamente significativa, como:
•Incapacidad de tomar medicación oral.
•Necesidad de alimentación IV.
•Intervenciones quirúrgicas previas que afecten a la absorción, como una resección gástrica total.
•Tratamiento por úlcera péptica activa en los seis últimos meses.
•Hemorragia digestiva activa, demostrada por hematemesis, hematoquecia o melena en los tres últimos meses, sin signos de resolución documentada mediante endoscopia o colonoscopia
•Lesión metastásica intraluminal con sospecha de hemorragia, enfermedad inflamatoria intestinal, colitis ulcerosa u otros trastornos digestivos asociados a un mayor riesgo de perforación o antecedentes de perforación digestiva.
•Síndrome de malabsorción.
•Enfermedad inflamatoria intestinal.
- Presenta un intervalo QT corregido por la frecuencia cardíaca (QTc) ≥ 480 ms.
- Tiene antecedentes de alguna de las siguientes enfermedades cardiovasculares en los 12 meses previos a la selección:
•Infarto de miocardio.
•Angina de pecho inestable.
•Angioplastia o implantación de prótesis endovasculares cardíacas.
•Injerto de derivación de arterias coronarias o periféricas.
•Insuficiencia cardíaca congestiva en clase III o IV según la New York Heart Association.
•Accidente cerebrovascular o accidente isquémico transitorio.
- Tiene antecedentes de trombosis venosa profunda o embolia pulmonar en los seis meses previos a la selección.
- Presenta hipertensión arterial mal controlada, definida como una presión arterial sistólica (PAS) ≥ 150 mm Hg y/o diastólica (PAD) ≥ 90 mm Hg.
- Tiene signos de la cicatrización inadecuada de heridas.
- Presenta un trastorno hemorrágico activo u otros antecedentes de episodios hemorrágicos importantes en los 30 días previos a la aleatorización.
- Ha tenido hemoptisis en las seis semanas previas a la aleatorización.
- Utiliza actualmente o se prevé que necesitará tratamiento con medicamentos o alimentos que sean inhibidores potentes conocidos del citocromo P450 (CYP3A4/5)
- Utiliza actualmente o se prevé que necesitará tratamiento con medicamentos que sean inductores potentes del CYP3A4/5
- Ha recibido un trasplante de órgano sólido previo.

E.5 End points

E.5.1

Primary end point(s)

- Progression Free Survival (PFS) per RECIST 1.1 as assessed by BICR
- Overall Survival (OS)

- Supervivencia sin progresión (SSP) por (RECIST 1.1) [1], evaluada mediante una revisión de imagen central independiente y enmascarada (RCIE).
- supervivencia global (SG)

E.5.1.1

Timepoint(s) of evaluation of this end point

First Interim Analysis (IA1)
- Timing: To be performed after enrollment completion, when all subjects have an opportunity to have at least 4 scheduled scans, and when approximately 50% of the final required OS events (or 198 deaths) have accrued. It is expected to be 21 months after study start. Approximately 380 PFS events are expected at IA1
- Purpose: Final analysis for PFS and IA1 for OS
Second Interim Analysis (IA2)
- Timing: To be performed when approximately 75% of the final required OS events (or 297 deaths) have accrued, expected to be 29 months after study start
- Purpose: IA2 for OS
Final analysis
- Timing: When approximately 396 deaths have accrued, expected to be 39 months after study start
- Purpose: Final analysis for OS (assuming not declared successful at the IA)

(AI1):
•Cuándo: Se realizará una vez completado el reclutamiento, cuando todos los sujetos hayan tenido la posibilidad de tener al menos 4 escáneres programados, y cuando aprox el 50% de eventos de (SG) (o 198 fallecimientos) hayan ocurrido. Se espera que sea después de 21 meses después de que haya empezado el estudio. Se esperan aprox 380 eventos de supervivencia sin progresión (SSP )en el AI1.
•Objetivo: Análisis final de la SSP y AI1 de la SG.
(AI2):
•Cuándo: Se realizará cuando aprox el 75% de eventos de SG (o 297 fallecimientos) hayan ocurrido, se espera que sea después de 29 meses de que haya empezado el estudio.
•Objetivo: AI2 de la (SG).
(AF)
•Cuándo: Cuando aprox 396 muertes hayan ocurrido, se espera que sea después de 39 meses de que haya empezado el estudio.

E.5.2

Secondary end point(s)

- To compare ORR, DOR and DCR per RECIST 1.1 as assessed by BICR
- To evaluate and compare safety and tolerability profiles
- To compare time to deterioration (TTD) based on the Functional Assessment of Cancer Therapy Kidney Symptom Index—Disease-Related Symptoms (FKSI-DRS) scale
- To assess the longitudinal score changes from baseline to 42 weeks as measured by European Organization for the Research and Treatment of Cancer (EORTC) QLQ-C30 global health status/quality of life scale

- Para comparar la ORR, DOR y DCR por RECIST 1.1 según la evaluación de BICR
- Evaluar y comparar los perfiles de seguridad y tolerabilidad
-Comparar el tiempo transcurrido hasta el deterioro (TTHD) según la escala FKSI-DRS (Índice de síntomas renales de la Evaluación funcional del tratamiento del cáncer–Síntomas relacionados con la enfermedad)
-Evaluar las variaciones de puntuación longitudinales entre el período basal y la semana 42 medidas mediante la escala de estado de salud general/calidad de vida del cuestionario QLQ-C30 de la Organización Europea para la Investigación y el Tratamiento del Cáncer (EORTC)

E.5.2.1

Timepoint(s) of evaluation of this end point

- PFS (primary testing), OS, ORR: 21 months (IA1)
- OS, ORR: 29 months (IA2)
- OS, ORR: 39 months (FA)
- The safety endpoint will be evaluated at each IA and at the Final Analysis while the QoL endpoints will be evaluated at Final Analysis
- In addition, the DMC will review safety periodically (every 4 months in the first year and frequency may be reduced after one year if no unexpected safety signals occur)
- The multiplicity adjustment for these safety reviews will be described in the DMC charter

•SSP (pruebas primarias, SG, tasa de respuesta objetiva (TRO): 21 meses (AI1)
•SG, TRO: 29 meses (AI2)
•SG, TRO: 39 meses (Análisis final)
•Criterios de valoración de la seguridad será evaluado en cada análisis intermedio y en el análisis final mientras Criterios de valoración relativos a calidad de vida relacionada con la salud serán evaluados en el Análisis final.
•Además, el comité de vigilancia de los datos externo revisará la seguridad periódicamente (cada 4 meses el primer año y la frecuencia podrá reducirse después de un año si no ocurren señales de seguridad).
•El ajuste multidisciplinar para estas revisiones de seguridad se describirán en los estatutos del comité de vigilancia de los datos externo (DMC)

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

Yes

E.6.11

Pharmacogenomic

Yes

E.6.12

Pharmacoeconomic

Yes

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

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

sunitinib

Sunitinib

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

Brazil

Canada

Czech Republic

France

Germany

Hungary

Ireland

Italy

Japan

Korea, Republic of

Poland

Russian Federation

Spain

Taiwan

Ukraine

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 be concluded after the clinical cutoff for the final OS analysis has been achieved

El estudio concluirá cuando se alcance el punto de corte clínico para el análisis final de la SG

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

400

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

440

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

420

F.4.2.2

In the whole clinical trial

840

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)

After confirmation of PD, subjects may initiate any subsequent anticancer treatment at the discretion of the treating physician and the subject per local standard of care.

Tras la verificación o confirmación de la PE, los sujetos podrán iniciar cualquier tratamiento antineoplásico posterior a criterio del médico responsable del tratamiento y del sujeto con arreglo a la práctica local

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

2016-09-19

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2016-08-19

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

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