Clinical Trials Register

Summary
EudraCT Number:	2015-003607-30
Sponsor's Protocol Code Number:	AV-951-15-303
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2016-01-13
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

2015-003607-30

A.3

Full title of the trial

A Phase 3, Randomized, Controlled, Multi-Center, Open-Label Study to Compare Tivozanib Hydrochloride to Sorafenib in Subjects With Refractory Advanced Renal Cell Carcinoma

Estudio de Fase 3, aleatorizado, controlado, multicéntrico y abierto, para comparar el tivozanib clorhidrato frente al sorafenib en sujetos con carcinoma de células renales avanzado resistente al tratamiento

A.3.1

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

Phase 3 open-label study of tivozanib versus sorafenib in refractory renal cell carcinoma

Estudio de Fase 3 abierto de tivozanib clorhidrato frente al sorafenib para carcinoma de células renales.

A.4.1

Sponsor's protocol code number

AV-951-15-303

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	AVEO PHARMACEUTICALS, 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	AVEO PHARMACEUTICALS, 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	AVEO Pharma Ltd.
B.5.2	Functional name of contact point	AVEO pharma limited
B.5.3	Address:
B.5.3.1	Street Address	59-60 Thames St
B.5.3.2	Town/ city	Windsor
B.5.3.3	Post code	SL4 1TX
B.5.3.4	Country	United Kingdom
B.5.4	Telephone number	+3191391 3443
B.5.5	Fax number	+441753272001
B.5.6	E-mail	clinicaltrialinfo@aveooncology.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	Yes
D.2.5.1	Orphan drug designation number	EMA/OD/148/09/T/02; EU/3/10/747
D.3 Description of the IMP
D.3.1	Product name	Tivozanib
D.3.2	Product code	AV-951
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	Tivozanib hydrochloride monohydrate
D.3.9.1	CAS number	682745-41-1
D.3.9.2	Current sponsor code	AV-951
D.3.9.3	Other descriptive name	TIVOZANIB
D.3.9.4	EV Substance Code	SUB64411
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	1.5
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: 2
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	Nexavar
D.2.1.1.2	Name of the Marketing Authorisation holder	Bayer Pharma AG
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	Yes
D.2.5.1	Orphan drug designation number	EU/3/13/1199
D.3 Description of the IMP
D.3.1	Product name	Sorafenib
D.3.2	Product code	L01XE05
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	SORAFENIB
D.3.9.1	CAS number	284461-73-0
D.3.9.4	EV Substance Code	SUB23139
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: 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	Yes
D.2.5.1	Orphan drug designation number	EMA/OD/148/09/T/02; EU/3/10/747
D.3 Description of the IMP
D.3.1	Product name	Tivozanib
D.3.2	Product code	AV-951
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	Tivozanib hydrochloride monohydrate
D.3.9.1	CAS number	682745-41-1
D.3.9.2	Current sponsor code	AV-951
D.3.9.3	Other descriptive name	TIVOZANIB
D.3.9.4	EV Substance Code	SUB64411
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.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 Renal Cell Carcinoma

Carcinoma de células renales avanzado

E.1.1.1

Medical condition in easily understood language

Advanced kidney cancer

Cáncer avanzado de riñón

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	18.1
E.1.2	Level	PT
E.1.2	Classification code	10050513
E.1.2	Term	Metastatic renal cell carcinoma
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

To compare the progression-free survival (PFS) of subjects with refractory advanced renal cell carcinoma (RCC) randomized to treatment with tivozanib hydrochloride (tivozanib) or sorafenib as assessed by blinded independent radiological review (IRR) of computerized tomography (CT) or magnetic resonance imaging
(MRI).

Comparar la supervivencia sin progresión (SSP) de los sujetos con carcinoma de células renales (CCR) avanzado resistente al tratamiento, asignados aleatoriamente a tratamiento con tivozanib clorhidrato (tivozanib) o sorafenib, según la evaluación de revisión radiológica independiente (RRI) de la tomografía computarizada (TC) o la resonancia magnética (RM), sin conocimiento del tratamiento asignado.

E.2.2

Secondary objectives of the trial

To compare the overall survival (OS) of subjects randomized to treatment with tivozanib or sorafenib.
To compare objective response rate (ORR) and duration of response (DoR) of subjects randomized to treatment with tivozanib or sorafenib.
To compare the safety and tolerability of tivozanib and sorafenib.

Comparar la supervivencia global (SG) de los sujetos asignados aleatoriamente a tratamiento con tivozanib o sorafenib.
Comparar la tasa de respuesta objetiva (TRO) y la duración de la respuesta (DR) de los sujetos asignados aleatoriamente a tratamiento con tivozanib o sorafenib.
Comparar la seguridad y la tolerabilidad de tivozanib y sorafenib.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. >/= 18-years of age.
2. Subjects with recurrent metastatic RCC who have failed 2 or 3 prior systemic regimens, one of which includes a VEGFR TKI other than sorafenib or tivozanib.
3. Subjects must have recovered from the AEs of prior therapy or returned to baseline, and be off all therapy for at least 2 weeks.
4. Histologically or cytologically confirmed RCC with a clear cell component (subjects with pure papillary cell tumor or other non-clear cell histologies, including collecting duct, medullary, chromophobe, mixed tumor containing predominantly sarcomatoid cells, and unclassified RCC are excluded).
5. Measurable disease per the Response Evaluation Criteria in Solid Tumors (RECIST) criteria Version 1.1.
6. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
7. Life expectancy ? 3 months.
8. If female and of childbearing potential, documentation of negative pregnancy test prior to enrollment.
9. Ability to give written informed consent and comply with protocol.

1. >/= 18 años de edad.
2. Sujetos con CCR metastásico recurrente en los que fallaron 2 o 3 regímenes sistémicos previos, uno de los cuales incluía un VEGFR TKI distinto de sorafenib o tivozanib.
3. Los sujetos deben haberse recuperado de los acontecimientos adversos del tratamiento previo o haber recuperado la situación basal, y haber dejado todos los tratamientos durante un mínimo de 2 semanas.
4. CCR confirmado histológicamente o citológicamente con un claro componente celular (se excluyen los sujetos con tumor puramente de células papilares u otras histologías celulares no claras, incluidas células de túbulo colector, medulares, cromófobas, tumor mixto que contiene células predominantemente sarcomatoides y CCR no clasificado).
5. Enfermedad medible según los criterios Response Evaluation Criteria in Solid Tumors (RECIST) versión 1.1.
6. Estado funcional del Eastern Cooperative Oncology Group (ECOG) de 0 o 1.
7. Esperanza de vida >/= 3 meses.
8. Si el sujeto es una mujer en edad fértil, se requiere una prueba de embarazo negativa antes del reclutamiento.
9. Capacidad para otorgar el consentimiento informado por escrito y para cumplir con los requisitos del protocolo.

E.4

Principal exclusion criteria

1. Prior treatment with sorafenib or tivozanib.
2. More than 3 prior regimens for metastatic RCC.
3. Known central nervous system (CNS) diseases other than stable, treated brain metastases, defined as primary CNS malignancies or CNS metastases
4. Significant cardiovascular disease
5. Significant thromboembolic or vascular disorders within 6 months prior to administration of first dose of study drug
6. Significant bleeding disorders
7. Currently active second primary malignancy
8. Pregnant or lactating females.

Participation in another interventional protocol.

1. Tratamiento previo con sorafenib o tivozanib.
2. Más de 3 regímenes previos para CCR metastásico.
3. Enfermedades del sistema nervioso central (SNC) conocidas aparte de metástasis cerebrales tratadas y estables, definidas como neoplasias primarias del SNC o metástasis del SNC.
4. Enfermedad cardiovascular importante.
5. Trastornos tromboembólicos o vasculares importantes en los 6 meses anteriores a la administración de la primera dosis de la medicación del estudio.
6. Trastornos hemorrágicos importantes.
7. Segunda neoplasia maligna primaria actualmente activa.
8. Mujeres embarazadas o en período de lactancia.

Participación en otro protocolo de intervención.

E.5 End points

E.5.1

Primary end point(s)

? To compare the PFS of subjects dosed with tivozanib with those subjects dosed with sorafenib.

Comparar la SSP de los sujetos tratados con tivozanib y de los sujetos tratados con sorafenib.

E.5.1.1

Timepoint(s) of evaluation of this end point

Analysis will be done at the time of the final PFS analysis.

El analisis se hará en el momento del análisis final de la SSP.

E.5.2

Secondary end point(s)

? To compare the OS between the 2 treatment arms by using stratified Log-rank test and the stratification factors included in the primary analysis.
? To analyze OS, ORR, and DoR using the investigator and independent radiological review assessments.

Comparar la SG entre los 2 grupos de tratamiento utilizando una prueba de rangos logarítmicos estratificada, los factores de estratificación incluidos en el análisis primario.
Los criterios de valoración secundarios (SG, TRO y DR) se analizarán utilizando las evaluaciones del investigador y la revisión radiológica independiente.

E.5.2.1

Timepoint(s) of evaluation of this end point

The interim OS analysis will be done at the time of the final PFS analysis.
The final OS analysis will be performed when all subjects have been lost to follow-up, have withdrawn consent, or have died, or when all subjects in follow-up have been on-study for at least 2 years, whichever occurs first.

El análisis intermedio de la SG se hará en el momento del análisis final de la SSP.
El análisis final de la SG se realizará cuando todos los sujetos se hayan perdido para el seguimiento, hayan retirado su consentimiento o hayan fallecido, o cuando todos los sujetos en seguimiento hayan estado en el estudio durante al menos 2 años, lo que suceda antes.

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

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

Yes

E.6.13.1

Other scope of the trial description

Tolerability

Tolerabilidad

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)

Yes

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

Australia

Belgium

Canada

Czech Republic

Denmark

France

Germany

Hungary

Israel

Italy

New Zealand

Poland

Spain

Sweden

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

End of the trial - when all subjects have been lost to follow-up, have withdrawn consent, or have died, or when all subjects in follow-up have been on-study for at least 2 years, whichever occurs first.

Fin del estudio cuando todos los sujetos se hayan perdido para el seguimiento, hayan retirado su consentimiento o hayan fallecido, o cuando todos los sujetos en seguimiento hayan estado en el estudio durante al menos 2 años, lo que suceda antes.

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

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

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

161

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

161

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

117

F.4.2.2

In the whole clinical trial

322

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)

Subjects with documented stable disease or an objective response may continue to receive therapy at the same dose and schedule until disease progression or unacceptable toxicities occur, or if other withdrawal criteria are met.

Los sujetos con enfermedad estable documentada o una respuesta objetiva pueden continuar recibiendo tratamiento con la misma dosis y posología hasta progresión de la enfermedad o la aparición de reacciones adversas inaceptables, o si se cumplen otros criterios de retirada.

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

2016-02-16

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2016-02-09

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2021-06-02

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