Clinical Trials Register

Summary
EudraCT Number:	2009-013407-66
Sponsor's Protocol Code Number:	AV-951-09-901
National Competent Authority:	Hungary - National Institute of Pharmacy
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2014-01-14
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

Hungary - National Institute of Pharmacy

A.2

EudraCT number

2009-013407-66

A.3

Full title of the trial

A Rollover Protocol to Allow Continued Access to Tivozanib Hydrochloride (AV-951) for Subjects Enrolled in Other Tivozanib Hydrochloride Protocols

Kiterjesztett vizsgálati terv mindazon betegek további tivozanib hidroklorid (AV-951) készítménnyel történő ellátására, akik különböző vizsgálatokban tivozanib hidrokloridot kaptak

A.3.1

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

Study to continue giving Tivozanib to subject participating in other studies with Tivozanib

Vizsgálati terv mindazon betegek további tivozanib hidroklorid készítménnyel történő ellátására, akik különböző vizsgálatokban tivozanib hidrokloridot kaptak

A.4.1

Sponsor's protocol code number

AV-951-09-901

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT01369433

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 Pharmaceuticals, Inc.
B.5.2	Functional name of contact point	Barbara Fielman
B.5.3	Address:
B.5.3.1	Street Address	650 East Kendall Street
B.5.3.2	Town/ city	Cambridge
B.5.3.3	Post code	MA 02142
B.5.3.4	Country	United States
B.5.4	Telephone number	+1617299-5902
B.5.5	Fax number	+1617995-4827
B.5.6	E-mail	bfielman@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	EU/3/10/747
D.3 Description of the IMP
D.3.1	Product name	Tivozanib hydrochloride
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
D.3.9.1	CAS number	475108-18-0
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	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: 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	Yes
D.2.5.1	Orphan drug designation number	EU/3/10/747
D.3 Description of the IMP
D.3.1	Product name	Tivozanib hydrochloride
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
D.3.9.1	CAS number	475108-18-0
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	1.0
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	EU/3/10/747
D.3 Description of the IMP
D.3.1	Product name	Tivozanib hydrochloride
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
D.3.9.1	CAS number	475108-18-0
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.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

Renal Cell Carcinoma Stage III,
Renal Cell Carcinoma Stage IV,
Metastatic Renal Cell Carcinoma

vese karcinóma

E.1.1.1

Medical condition in easily understood language

renal cancer

vese daganat

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	16.1
E.1.2	Level	LLT
E.1.2	Classification code	10038400
E.1.2	Term	Renal carcinoma stage IV
E.1.2	System Organ Class	100000004864

E.1.2 Medical condition or disease under investigation

E.1.2	Version	16.1
E.1.2	Level	LLT
E.1.2	Classification code	10038399
E.1.2	Term	Renal carcinoma stage III
E.1.2	System Organ Class	100000004864

E.1.2 Medical condition or disease under investigation

E.1.2	Version	16.1
E.1.2	Level	LLT
E.1.2	Classification code	10050076
E.1.2	Term	Metastatic renal carcinoma
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

To allow continued access to tivozanib for subjects who have participated in other tivozanib (monotherapy or combination) protocols, who are tolerating study drug and displaying clinical benefit and to provide access to tivozanib hydrochloride as a treatment option for subjects who received sorafenib in study AV-951-09-902 and were tolerating sorafenib and displaying clinical benefit at the time of study termination.

•További hozzáférést biztosítani a tivozanib hidrokloridhoz olyan betegeknek, akik más tivozanib hidrokloriddal történő klinikai vizsgálatokban már részt vettek (monoterápiaként, kombinációban, vagy másik karról átlépve kapták a szert), jól tolerálták a vizsgálati készítményt, és klinikailag értékelhető javulást mutattak.
•Kezelési lehetőségként biztosítani a tivozanib hidrokloridot olyan betegeknek, akik az AV-951-09-902 vizsgálatban sorafenibet kaptak, azt jól tolerálták, és a vizsgálat befejezésekor klinikailag értékelhető javulást mutattak

E.2.2

Secondary objectives of the trial

To assess long-term safety and tolerability in subjects who continue on tivozanib

Kiértékelni olyan betegek hosszútávon tapasztalt nemkívánatos eseményeit és súlyos nemkívánatos eseményeit, akik tovább szedik a tivozanib hidrokloridot.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. The subject must have received tivozanib hydrochloride while enrolled in another protocol, must be tolerating study drug and must currently display clinical benefit. The length of time that a subject must be on the parent protocol before rolling over to this protocol will be dictated by the parent protocol.
a. Subjects who received tivozanib hydrochloride at any time while on parent protocol AV-951-12-205, regardless of sequence, may enroll if they tolerated and displayed clinical benefit while receiving tivozanib hydrochloride.
b. Subjects receiving sorafenib in Study AV-951-09-902 who were tolerating sorafenib and displaying clinical benefit at the time of study termination may initiate tivozanib hydrochloride as a treatment option.
2. If female and of childbearing potential, documentation of negative pregnancy test prior to enrollment (i.e. before the first dose of tivozanib hydrochloride in this protocol).
3. Ability to give written informed consent.

1.Egy másik protokollban bevont betegként tivozanib hidrokloridot kellett kapnia, jól kell tolerálnia a vizsgálati készítményt és jelenleg is klinikailag értékelhető javulást kell mutatnia. Hogy mennyi ideje kellett kapnia a betegnek a készítményt, mielőtt átkerülhet ebbe a vizsgálatba, az az eredeti vizsgálati protokolltól függ.
a.Bevonhatók azok a vizsgálati alanyok, akiket eredetileg az AV-951-12-205 vizsgálatba vontak be és annak keretében bármikor kaptak tivozanib hidrokloridot függetlenül az egymásutániságtól, azt jól tolerálták és a tivozanib hidroklorid kezelés hatására klinikailag értékelhető javulást értek el.
b.Azok a betegek, akik az AV-951-09-902 vizsgálatban sorafenibet kaptak, és azt jól tolerálták, illetve klinikailag értékelhető javulást értek el, a vizsgálat lezárásakor kezdeményezhetik, hogy kezelésként tivozanib hidrokloridot kaphassanak.
2.Ha a beteg fogamzóképes nő, akkor a bevonás előtt dokumentumokkal köteles igazolni, hogy a terhességi tesztje negatív (azaz még mielőtt megkapná ebben a klinikai vizsgálatban az első tivozanib hidroklorid dózisát).
3.A beteg képes írásos beleegyező nyilatkozatot adni.

E.4

Principal exclusion criteria

1. > 4 weeks since discontinuation of study drug treatment on a previous AVEO-sponsored clinical trial.
a. For subjects initiating tivozanib hydrochloride (ie receiving sorafenib and demonstrating tolerability and clinical benefit on Study AV-951-09-902 at the time of study termination), > 4 weeks since last dose of sorafenib, unless discussed with Sponsor.
2. If female, pregnant or lactating.
3. Sexually active male and pre-menopausal female subjects (and their partners) unless they agree to use adequate contraceptive measures, while on study and for 45 days after the last dose of study drug. All fertile male and female subjects (and their partners) must agree to use a highly effective method of contraception. Highly effective birth control includes (a) IUD plus one barrier method; (b) oral, implantable or injectable contraceptive plus one barrier method; or (c) 2 barrier methods. Effective barrier methods are male or female condoms, diaphragms, and spermicides (creams or gels that contain a chemical to kill sperm).
4. Uncontrolled hypertension: systolic blood pressure > 140 mmHg or diastolic blood pressure >90 mmHg documented on 2 consecutive measurements taken at least 24 hours apart.
5. Unhealed wounds (including active peptic ulcers).
6. Serious/active infection or infection requiring parenteral antibiotics.
7. Life-threatening illness or organ system dysfunction compromising safety evaluation.
8. Psychiatric disorder, altered mental status precluding informed consent or necessary testing.
9. Inability to comply with protocol requirements.

1.Akiknél több mint 4 hét telt el azóta, hogy egy korábbi AVEO szponzorált vizsgálatban abbamaradt a vizsgálati készítménnyel folytatott kezelés
a.Ha a beteg tivozanib hidrokloridra szeretne áttérni (azaz a beteg eddig sorafenibet kapott, azt jól tolerálta, és a vizsgálat befejezésekor klinikailag értékelhető javulást ért el az AV-951-09-902 vizsgálat zárásakor) és több mint 4 hét telt el az utolsó adag sorafenib óta, kivéve, ha a szponzorral történt megbeszélés után más döntés nem születik.
2.Ha a nőbeteg terhes, vagy szoptat.
3.A szexuálisan aktív férfiak és a pre-menopauzában levő nők (és partnereik), ha nem egyeznek bele, hogy megfelelő fogamzásgátlást alkalmazzanak mindaddig, míg részt vesznek a vizsgálatban és további 45 napig a vizsgálati készítmény utolsó adagjátkövetően. Minden nemzőképes férfi- és fogamzóképes nőbetegnek (és partnereiknek) vállalniuk kell, hogy igen megbízható fogamzásgátlást alkalmaznak. Ilyen megbízható fogamzásgátlás lehet a (a) méhen belüli eszköz (IUD) egy barrier módszerrel együtt; (b) szájon át szedett, implantált, vagy injekcióban adott fogamzásgátló egy barrier módszerrel együtt; vagy (c) egyidejűleg két barrier módszer. Hatékony barrier módszernek tekinthető a férfi, vagy női kondom, a pesszárium és spermicid krémek, vagy gélek, amelyek olyan vegyi anyagot tartalmaznak, amelyek elölik a spermiumokat.
4.Kezeletlen magas vérnyomás: a szisztolés vérnyomás magasabb, mint 140 Hgmm, vagy a diasztolés vérnyomás több, mint 90 Hgmm két egymást követő mérés alkalmával, melyek között legalább 24 óra telt el .
5.Nem gyógyuló sebek (ideértve az aktív gyomorfekélyt).
6.Súlyos/aktív fertőzés, illetve parenterális antibiotikumot igénylő fertőzés.
7.Életveszélyes betegség, vagy szervrendszeri működészavar, amely veszélyezteti a biztonságossági értékelést.
8.Pszichiátriai rendellenesség, megváltozott elmeállapot, amely nem teszi lehetővé, hogy a beteg beleegyező nyilatkozatot adjon, vagy elvégezzék a szükséges teszteket
9.A beteg képtelen betartani a vizsgálat terv előírásait.

E.5 End points

E.5.1

Primary end point(s)

Not Applicable

E.5.1.1

Timepoint(s) of evaluation of this end point

Not Applicable

E.5.2

Secondary end point(s)

Not Applicable

E.5.2.1

Timepoint(s) of evaluation of this end point

Not Applicable

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

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

allow continued access to tivozanib

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

E.8.1.1

Randomised

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

Yes

E.8.4

The trial involves multiple sites in the Member State concerned

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

Bulgaria

Canada

France

Romania

Chile

Hungary

India

Poland

Russian Federation

Serbia

Ukraine

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

The end of the study is the last treatment visit of the last subject at the last site.

LVLS

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:

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

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 either experiencing unacceptable toxicities or with documented disease progression will be discontinued from further participation in this study.

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

2014-02-26

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2014-01-30

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2015-06-23

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Clinical trials