Clinical Trials Register

Summary
EudraCT Number:	2014-002508-26
Sponsor's Protocol Code Number:	IRFMN-RCC-6691
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2015-01-09
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

Italy - Italian Medicines Agency

A.2

EudraCT number

2014-002508-26

A.3

Full title of the trial

Outcome-related factors in patients with metastatic renal cell carcinoma treated with everolimus after failure of a first-line treatment with VEGF inhibitor

Fattori associati all’esito in pazienti con carcinoma renale metastatico trattati con everolimus dopo fallimento di una prima linea di terapia con un inibitore di VEGF

A.3.1

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

Evaluation of unfavourable outcome-related factors in patients affected by renal cell cancer in treatment with everolimus and previously treated with a VEGF inhibitor (i.e. sunitinib, sorafenib,pazopanib, or bevacizumab+interferon)

Valutazione di fattori associati ad un esito sfavorevole in pazienti con carcinoma delle cellule renali in trattamento con everolimus e precedentemente trattati con un inibitore di VEGF (cioè sunitinib, sorafenib,pazopanib, o bevacizumab+interferon)

A.3.2

Name or abbreviated title of the trial where available

ORCHIDEE

A.4.1

Sponsor's protocol code number

IRFMN-RCC-6691

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	IRCCS - Istituto di Ricerche Farmacologiche "Mario Negri"
B.1.3.4	Country	Italy
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Novartis Farma S.p.A
B.4.2	Country	Italy
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	IRCCS - Istituto di Ricerche Faramcologiche "Mario Negri"
B.5.2	Functional name of contact point	Clinical Research laboratory
B.5.3	Address:
B.5.3.1	Street Address	via privata Giuseppe La Masa
B.5.3.2	Town/ city	Milan
B.5.3.3	Post code	20156
B.5.3.4	Country	Italy
B.5.4	Telephone number	00390239014661
B.5.6	E-mail	irene.desimone@marionegri.it

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	Afinitor
D.2.1.1.2	Name of the Marketing Authorisation holder	Novartis Europharma LTD
D.2.1.2	Country which granted the Marketing Authorisation	Italy
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	everolimus
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	Afinitor
D.3.9.1	CAS number	159351-69-6
D.3.9.3	Other descriptive name	EVEROLIMUS
D.3.9.4	EV Substance Code	SUB02065MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	10 to 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	Yes
D.3.11.13.1	Other medicinal product type	antineoplastic agent

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

metastatic renal cell carcinoma in progression after a first line treatment with a VEGF inhibitor.

carcinoma renale metastatico, in progressione dopo una prima linea di trattamento con un inibitore di VEGF

E.1.1.1

Medical condition in easily understood language

renal cell carcinoma in progression after one treatment with a vascular endothelial growth factor inhibitor

tumore delle cellule renali in progressione dopo trattamento con un inibitore del fattore di crescita dell'epitelio vascolare

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	17.1
E.1.2	Level	PT
E.1.2	Classification code	10067946
E.1.2	Term	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 identify factors predictive of a favourable outcome, in terms of survival free from an unfavourable event, in patients treated with everolimus as second line treatment for metastatic renal cell carcinoma (mRCC) after failure of a first-line treatment with a vascular endothelial growth factor (VEGF) inhibitor.

Identificare fattori predittivi di sopravvivenza libera da un evento non favorevole in pazienti trattati con everolimus in seconda linea per carcinoma renale metastatico dopo fallimento di una prima linea con un inibitore del fattore di crescita dell'endotelio vascolare (vascular endothelial growth factor, VEGF)

E.2.2

Secondary objectives of the trial

To evaluate:
• efficacy in terms of progression free survival of everolimus as second line treatment;
• health related quality of life (HRQoL), as measured by the EQ-5D questionnaire;
• drug-related toxicity, assessed by the National Cancer Institute-Common Terminology Criteria for adverse events (NCI-CTCAE), version 4.03;
• treatment compliance.

Valutare:
• L’efficacia in termini di sopravvivenza libera da progressione;
• La qualità di vita correlata alla salute (HRQoL) valutata mediante il questionario QoL EQ-5D;
• La tollerabilità, valutata secondo la scala del National Cancer Institute-Common Terminology Criteria for adverse events (NCI-CTCAE);
• La compliance al trattamento.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Male or female, aged 18 years or older, with histologically or cytologically confirmed mRCC (clear cell or not clear cell);
2. ECOG-PS <2;
3. With target and/or non-target lesions according to RECIST 1.1;
4. Following failure of a previous treatment with VEGF-targeted therapy (e.g. sunitinib, sorafenib, pazopanib, or bevacizumab+interferon);
5. For whom a decision has been taken to initiate everolimus treatment or patient currently receiving treatment with everolimus by a period of time ≤30 days;

1. Uomini o donne di età >18 anni con diagnosi istologica o citologica di carcinoma renale metastatico (a cellule chiare o meno);
2. ECOG Performance Status ≤2;
3. Presenza di lesioni target e/o non target secondo i criteri RECIST 1.1;
4. Precedente fallimento di una prima linea di terapia con inibitore di VEGF (ad esempio sunitinib, sorafenib, pazopanib, o bevacizumab+interferone);
5. Decisione di iniziare un trattamento con everolimus o pazienti attualmente in cura con everolimus da un periodo di tempo ≤ a 30 giorni;

E.4

Principal exclusion criteria

1. Previous treatment with everolimus or at the date of written informed consent provision receiving everolimus by more than 30 days;
2. Symptomatic central nervous system metastases. Patients may be eligible if the central nervous system
metastases have been adequately treated (surgery or radiotherapy), and do not require ongoing
corticosteroids for control of symptoms and have had no evidence of progression for at least three months;
3. Treatment with an investigational agent in the past 4 weeks;
4. Any of the following in the last year: myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, cerebrovascular accident or transient ischemic attack or pulmonary embolism;
5. Ongoing grade ≥2 cardiac dysrhythmias, atrial fibrillation of any grade or prolongation of the corrected QT interval to >450 msec for males or >470 msec for females;
6. Pregnancy (negative pregnancy test required for women of child-bearing potential), breast feeding;

1. Precedente trattamento con everolimus o pazienti che, al momento della firma del consenso informato, siano in trattamento con everolimus da più di 30 giorni;
2. Metastasi sintomatiche a livello del sistema nervoso centrale, se non adeguatamente trattate (chirurgia o radioterapia), che richiedano l’utilizzo di corticosteroidi per il controllo dei sintomi e con evidenza di progressione negli ultimi 3 mesi;
3. Trattamento con un altro agente sperimentale nelle ultime 4 settimane;
4. Una delle seguenti condizioni, se verificatesi nell’ultimo anno: infarto miocardico, angina grave/instabile, intervento di bypass coronarico da arteria periferica, insufficienza cardiaca congestizia sintomatica, ictus cerebrovascolare o attacco ischemico transitorio o embolia polmonare;
5. Concomitanti aritmie cardiache di grado >2, fibrillazione atriale di qualsiasi grado o prolungamento dell’intervallo QT corretto (QTc) a >450 msec per gli uomini e >470 msec per le donne;
6. Gravidanza (per le donne in età fertile è richiesto un test di gravidanza con esito negativo) o allattamento;

E.5 End points

E.5.1

Primary end point(s)

Survival free from an unfavourable event, calculated in each patient as the time from the date of written informed consent provision to the date of occurrence of the first among the following events: death from any cause, disease progression (according to RECIST 1.1), interruption of everolimus due to toxicity and/or deterioration of clinical conditions, and HRQoL deterioration (7-point decrease from baseline evaluation on the EQ-5D visual analogue scale).

Sopravvivenza libera da un evento non favorevole, calcolata in ciascun paziente come il tempo intercorso tra la data di firma del consenso informato e la data d’insorgenza del primo tra i seguenti eventi: morte per qualsiasi causa, progressione di malattia (secondo i criteri RECIST 1.1), interruzione di trattamento per tossicità e/o scadimento delle condizioni cliniche e/o peggioramento della qualità di vita correlata alla salute (diminuzione di sette punti rispetto al basale sulla scala QoLEQ-5D VAS);

E.5.1.1

Timepoint(s) of evaluation of this end point

At the end of the study, i.e. when the target number of events is reached and the last patient enrolled events is reached and the last patient, is followed for at least 12 months

Alla fine dello studio, ossia quando è stato raggiunto il numero di eventi e quando l'ultimo paziente arruolato sarà stato seguito per almeno 12 mesi

E.5.2

Secondary end point(s)

• Progression free survival, calculated in each patient as the time from the date of written informed consent provision to the date of first progression or death from any cause, whichever comes first;
• EQ-5D questionnaire score;
• Treatment compliance;
• Maximum toxicity grade experienced by each patient for each specific toxicity, giving the frequency of patients experiencing adverse events that are recorded as grade 3-5 (also grade 2 for neurotoxicity);
• Type and frequency of serious adverse reactions.

• Sopravvivenza libera da progressione, calcolata in ciascun paziente come il tempo intercorso tra la data di firma del consenso informato e la data di progressione o morte per ogni causa;
• Qualità di vita secondo il questionario EQ-5D;
• Compliance al trattamento;
• Grado massimo di tossicità registrato per ogni paziente e per singolo tipo di tossicità, espressa mediante la percentuale di pazienti con eventi avversi di grado 3-5 (grado 2 per la neurotossicità);
• Tipo e frequenza di reazioni avverse serie

E.5.2.1

Timepoint(s) of evaluation of this end point

At the end of the study, i.e. when the target number of events is reached and the last patient enrolled events is reached and the last patient, is followed for at least 12 months

Alla fine dello studio, ossia quando è stato raggiunto il numero di eventi e quando l'ultimo paziente arruolato sarà stato seguito per almeno 12 mesi

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

E.6.5

Efficacy

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

predictive factors evaluation

ricerca di fattori predittivi

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)

E.7.4

Therapeutic use (Phase IV)

Yes

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

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

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

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 study will be closed when the target number of events is reached and the last patient enrolled events is reached and the last patient, is followed for at least 12 months

la fine dello studio è definita come il raggiungimento del numero pianificato di eventi, quando l'ultimo paziente arruolato sarà stato seguito per almeno 12 mesi

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:

170

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

200

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)

Treatment or care after a subject has ended his/her participation in the trial is not different from normal clincial practice

Il trattamento di un paziente che ha completato la sua partecipazione allo studio non si discosta dalla normale pratica clinica

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

2015-02-04

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2015-02-10

P. End of Trial
P.	End of Trial Status	Completed

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