Clinical Trials Register

Summary
EudraCT Number:	2015-002419-14
Sponsor's Protocol Code Number:	IRST189.04
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2018-09-19
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

Italy - Italian Medicines Agency

A.2

EudraCT number

2015-002419-14

A.3

Full title of the trial

Phase II study of oral PRednisone 5 mg bid plus EVerolimus in patients with metastatic renal cell cancer after failure of vascular endothelial growth factor receptor-tyrosine kinase inhibitors (PREV study)

A.3.1

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

Studio di fase II che prevede l’utilizzo di PRednisone orale 5 mg due volte al giorno ed EVerolimus in pazienti con carcinoma renale metastatico dopo il fallimento di trattamento con inibitori del recettore tirosin-chinasico del fattore di crescita dell'endotelio vascolare

A.3.2

Name or abbreviated title of the trial where available

A.4.1

Sponsor's protocol code number

IRST189.04

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	ISTITUTO SCIENTIFICO ROMAGNOLO PER LO STUDIO E LA CURA DEI TUMORI (IRST) S.R.L. IRCCS
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	IRST IRCCS - Italia
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	IRST IRCCS
B.5.2	Functional name of contact point	Centro di Coordinamento Studi IRST
B.5.3	Address:
B.5.3.1	Street Address	Dipartimento di Oncologia ed Ematologia, Ospedale Civile S. Maria delle Croci, viale Randi, 5
B.5.3.2	Town/ city	Ravenna
B.5.3.3	Post code	48121
B.5.3.4	Country	Italy
B.5.4	Telephone number	+39 0544 285813
B.5.5	Fax number	+39 0544 285330
B.5.6	E-mail	cc.ubsc@irst.emr.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	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.4	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	EVEROLIMUS
D.3.9.2	Current sponsor code	EVEROLIMUS_IRSTIRCCS
D.3.9.3	Other descriptive name	EVEROLIMUS
D.3.9.4	EV Substance Code	SUB176818
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	10
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	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
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	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	PREDNISONE_IRSTIRCCS
D.3.2	Product code	PREDNISONE_IRSTIRCCS
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	PREDNISONE
D.3.9.2	Current sponsor code	PREDNISONE_IRSTIRCCS
D.3.9.3	Other descriptive name	PREDNISONE
D.3.9.4	EV Substance Code	SUB176819
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	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
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

metastatic renal cell cancer

carcinoma renale metastatico

E.1.1.1

Medical condition in easily understood language

metastatic renal cell cancer

carcinoma renale metastatico

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	20.0
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

E.2 Objective of the trial

E.2.1

Main objective of the trial

To evaluate the safety and tolerability of prednisone 5 mg bid and everolimus 10 mg/day in patients with metastatic renal cell cancer.

Valutare la sicurezza e la tollerabilità di prednisone 5 mg bid in associazione con everolimus 10 mg/die nei pazienti con carcinoma renale metastatico.

E.2.2

Secondary objectives of the trial

To evaluate the activity and the clinical outcome of these patients.
Exploratory objectives:
To evaluate the influence of prednisone on trough concentration of everolimus and correlation with the incidence of side effects, in particular stomatitis and non-infectious pneumonitis.
Infiammation markers such as pentraxin 3 (PTX3), IL-6, TGF-β and neutrophil-lymphocyte ratio will be correlated with clinical outcome (ORR, PFS, OS).

Valutare l'attività e l’outcome clinico in questi pazienti.
Obiettivi esplorativi:
Valutare l'influenza del prednisone sulla concentrazione minima di everolimus e la correlazione con l'incidenza di effetti collaterali, in particolare stomatiti e polmoniti non infettive.
Marcatori di infiammazione come pentraxina 3 (PTX3), IL-6, TGF-β ed il rapporto neutrofili-linfociti saranno inoltre correlati con l’esito clinico (ORR, PFS, OS).

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

- Patients with renal cell carcinoma who failed at least one VEGFR TKI
- Patients with adequate bone marrow function
- Patients with adequate liver function
- Patients with adequate renal function

- pazienti con carcinoma renale che hanno fallito almeno una linea precedente di trattamento VEGFR TKI
- pazienti con adeguata funzionalità midollare
- pazienti con adeguata funzionalità epatica
- pazienti con adeguata funzionalità renale

E.4

Principal exclusion criteria

- CNS disease OR patients with presence or history of central nervous system (CNS) lymphoma
- Patients receiving chronic, systemic treatment with corticosteroids or another immunosuppressive agent (except corticosteroids with a daily dosage equivalent to prednisone ≤ 20 mg for adrenal insufficiency). However, patients receiving corticosteroids must be on a stable dose for ≥ 4 weeks prior to the first dose of everolimus. Topical or inhaled corticosteroids are permitted.
- Patients with a known hypersensitivity to everolimus or other rapamycins (sirolimus, temsirolimus) or to its excipients
- Patients with uncontrolled hyperlipidemia (≥ Grade 3 hyperlipidemia despite optimal supportive medical therapy)
- Patients with an active, bleeding diathesis
- Previous organ transplantation
- Patients who have any severe and/or uncontrolled medical conditions or other conditions that could affect their participation in the study

- malattie del sistema nervoso centrale o pazienti con presenza o storia di linfoma del sistema nervoso centrale (SNC)
- pazienti che ricevono trattamento cronico con corticosteroidi sistemici o altri farmaci immunosoppressivi (ad eccezione di corticosteroidi con un dosaggio giornaliero equivalente a ≤20 mg prednisone per l'insufficienza surrenalica). Tuttavia, i pazienti trattati con corticosteroidi devono essere in trattamento ad un dosaggio stabile per ≥ 4 settimane prima della prima dose di everolimus. I corticosteroidi topici o per via inalatoria sono consentiti.
- pazienti con ipersensibilità nota a everolimus o ad altre rapamicine (sirolimus, temsirolimus) o ai suoi eccipienti
- pazienti con iperlipidemia non-controllata (≥ grado 3 iperlipidemia nonostante una terapia medica di supporto ottimale)
- pazienti con diatesi emorragica attiva
- precedente che hanno subito trapianto di organi
- pazienti che hanno condizioni mediche gravi e/o non controllate o altre condizioni che potrebbero pregiudicare la loro partecipazione allo studio

E.5 End points

E.5.1

Primary end point(s)

evaluate the incidence of grade ≥ 2 stomatitis and non-infectious pneumonitis in RCC patients treated with prednisone 5 mg bid and everolimus 10 mg/day.

valutare l'incidenza di stomatiti e polmoniti non infettive di grado ≥ 2 nei pazienti con carcinoma renale metastatico trattati con prednisone 5 mg bid e everolimus 10 mg / die.

E.5.1.1

Timepoint(s) of evaluation of this end point

3 years

3 anni

E.5.2

Secondary end point(s)

To evaluate overall response rate, PFS and OS in this patient population.
Exploratory Endpoints: To evaluate the influence of prednisone on trough concentration of everolimus and correlation with the incidence of side effects, in particular stomatitis and non-infectious pneumonitis.
Infiammation markers such as pentraxin 3 (PTX3), IL-6, TGF-β and neutrophil-lymphocyte ratio will be correlated with clinical outcome (ORR, PFS, OS).

Valutare il tasso di risposta globale, PFS e OS in questa popolazione di pazienti.
Endpoint esplorativi: valutare l'influenza del prednisone sulla concentrazione minima di everolimus e la correlazione con l'incidenza di effetti collaterali, in particolare stomatiti e polmoniti non infettive.
Marcatori di infiammazioni come l'pentraxina 3 (PTX3), IL-6, TGF-β ed il rapporto neutrofili-linfociti saranno correlati con l'esito clinico (ORR, PFS, OS).

E.5.2.1

Timepoint(s) of evaluation of this end point

3 years

3 anni

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

To evaluate the influence of prednisone on trough concentration of everolimus and correlation with the incidence of side effects, in particular stomatitis and non-infectious pneumonitis.
Infiammation markers such as pentraxin 3 (PTX3), IL-6, TGF-β and neutrophil-lymphocyte ratio will be correlated with clinical outcome (ORR, PFS, OS).

Valutare l'influenza del prednisone sulla concentrazione minima di everolimus e la correlazione con l'incidenza di effetti collaterali, in particolare stomatiti e polmoniti non infettive.
Marcatori di infiammazione come pentraxina 3 (PTX3), IL-6, TGF-β ed il rapporto neutrofili-linfociti saranno inoltre correlati con l’esito clinico (ORR, PFS, OS).

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)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

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

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

Information not present in EudraCT

E.8.1.6

Cross over

Information not present in EudraCT

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.8.5.1

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

E.8.6.2

Trial being conducted completely outside of the EEA

Information not present in EudraCT

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

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

Number of subjects for this age range:

F.1.1.1

In Utero

Information not present in EudraCT

F.1.1.2

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

Information not present in EudraCT

F.1.1.3

Newborns (0-27 days)

Information not present in EudraCT

F.1.1.4

Infants and toddlers (28 days-23 months)

Information not present in EudraCT

F.1.1.5

Children (2-11years)

Information not present in EudraCT

F.1.1.6

Adolescents (12-17 years)

Information not present in EudraCT

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

Yes

F.3.3.2

Women of child-bearing potential using contraception

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)

Assessments during follow-up (every 12 weeks ± 2 weeks):
- visit
- Vital parameters (pressure, temperature and heart rate), weight
- Laboratory exams as clinical practice
- Cancer therapies
- chest / abdomen CT scan or MRI (in patients without documented disease progression)

Valutazioni durante il Follow-up (ogni 12 settimane ± 2 settimane):
- visita
- parametri vitali (pressione, frequenza cardiaca e temperatura), peso
- esami di laboratorio come da pratica clinica
- terapie antitumorali
- TAC o risonanza magnetica di torace/addome (in pazienti per i quali non sia stata documentata progressione di malattia)

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

2015-07-27

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2015-09-02

P. End of Trial
P.	End of Trial Status	Prematurely Ended

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