Clinical Trials Register

Summary
EudraCT Number:	2011-002887-26
Sponsor's Protocol Code Number:	CRAD001T2302
National Competent Authority:	Netherlands - Competent Authority
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2012-03-27
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

Expand All Collapse All

A. Protocol Information

A.1

Member State Concerned

Netherlands - Competent Authority

A.2

EudraCT number

2011-002887-26

A.3

Full title of the trial

A randomized, double-blind, multicenter, Phase III study of everolimus (RAD001) plus best supportive care versus placebo plus best supportive care in the treatment of patients with advanced NET of GI or lung origin

een gerandomiseerde, dubbelblinde, multicentrum, fase 3 studie naar everolimus (RAD001) met maximaal ondersteunende therapie in vergelijking met placebo met maximaal ondersteunende therapie plus in patiënten met gevorderde NET afkomstig uit GI of long.

A.3.1

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

A study of everolimus plus best supportive care versus placebo plus best supportive care in the treatment of patients with advanced neuroendocrine cancer of gastrointestinal or lung origin

een studie naar everolimus met maximaal ondersteunende therapie in vergelijking met placebo met maximaal ondersteunende therapie bij patienten met gevorderde NET uit het maagdarm kanaal of long zijn ontstaan

A.3.2

Name or abbreviated title of the trial where available

RADIANT-4

A.4.1

Sponsor's protocol code number

CRAD001T2302

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	Novartis Pharma Services AG
B.1.3.4	Country	Switzerland
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	Novartis Pharma Services AG
B.4.2	Country	Switzerland
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Novartis Pharma Ag
B.5.2	Functional name of contact point	Clinical Trial information Desk
B.5.3	Address:
B.5.3.1	Street Address	Forum 1, Novartis Campus
B.5.3.2	Town/ city	Basel
B.5.3.3	Post code	4056
B.5.3.4	Country	Switzerland
B.5.4	Telephone number	004161 3241111
B.5.5	Fax number	004161 3248001
B.5.6	E-mail	clinicaltrial.enquiries@novartis.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	Afinitor®
D.2.1.1.2	Name of the Marketing Authorisation holder	Novartis Europharm Limited
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	Everolimus
D.3.2	Product code	RAD001
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.3.9.1	CAS number	159351-69-6
D.3.9.2	Current sponsor code	RAD001
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	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.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Tablet
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Advanced neuroendocrine tumor (NET) of GI or lung origin

gevorderde neuroendrocriene tumor (NET) met GI of long origine

E.1.1.1

Medical condition in easily understood language

Advanced neuroendocrine cancer of gastrointestinal or lung origin

gevorderde neuroendrocriene kanker met gastrointestinaal of long afkomst

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	14.1
E.1.2	Level	PT
E.1.2	Classification code	10052399
E.1.2	Term	Neuroendocrine tumour
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

Determinate whether treatment with everolimus plus best supportive care prolongs PFS compared to placebo plus best supportive care in patients with advanced NET of GI or lung origin

Onderzoeken of behandeling met everolimus plus maximaal ondersteunende
therapie de PFS verlengt ten opzichte van placebo plus met maximaal ondersteunende
therapie in patienten met gevorderde NET met GI of long origine

E.2.2

Secondary objectives of the trial

Safety evaluation and tolerability of everolimus

veiligheid en verdraagzaamheid van everolimus

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1.Pathologically confirmed, well differentiated (G1 or G2), advanced (unresectable or metastatic), neuroendocrine tumor of GI or lung origin.
2.No history of and no active symptoms related to carcinoid syndrome (or other hypersecretory syndromes).
3.Patients treated with prior SSA and/or Interferon (IFN) may be included. These patients must discontinue treatment prior to the day of randomization as follows:
4.Radiological documented disease progression within 6 months prior to randomization
5.Measurable disease
6.WHO performance status ≤1
7.Adequate bone marrow, lifer and renal function
Other protocol-defined inclusion/exclusion criteria may apply

1. Pathologisch bevestigde, goed-gedifferentieerde (G1 of G2), gevorderde (niet operabel of gemetastaseerd) neuro endrocriene tumor uit long of gastro intestinale oorsprong
2. Geen geschiedenis van of aanwezigheid van symptomen van carcinoid syndroom
3. Behandeling naief patienten, patienten reeds behandeld met SSA, interferon of maximaal 1 lijn chemotherapie, en/of PRRT zijn toegestaan. Patienten met een eerdere behandeling moeten progressief geworden zijn tijdens of na de laatste behandeling
4. Voorgaande behandelingen moeten gestopt zijn voor de dag van randomisatie als volgt:
a) SSA behandeling minimaal 4 weken geleden
b) Interferon behandeling minimaal 4 weken geleden
c) chemotherapie minimaal 4 weken geleden
d) PRRT behandeling minimaal 6 maanden geleden
5. Radiologische documentatie van progressieve ziekte binnen 6 maanden voor randomisatie
6. Meetbare tumorleasies volgens RECIST 1.0 uit CT scan of MRI, met uitsluiting van leasies die eerder zijn behandeld, (percutaan, operatief of radiotherapeutisch), tenzij deze leasies overduidelijk progressief zijn.
7 WHO score van 0 of 1
8. adequate beenmerg functie waarbij ANC ≥1.5 x 109/L, trombocyten ≥100 x 109/L, Hb >9 g/dL;
9. Adequate lever functie vastgesteld door
a) totaal serum bilirubine ≤ 2.0 mg/dl
b)ALAT en ASAT ≤2.5x ULN (≤5x ULN in patienten met lever metastasen)
c) INR ≤2;
10 adequate nierfunctie waarbij serum creatinine ≤1.5x ULN
11 nuchter serum cholesterol ≤300 mg/dL of ≤7.75 mmol/L en triglyceriden ≤2.5x ULN
12 mannen of vrouwen ≥18 jaar
13 getekend informed consent voor aanvang van screening procedures

E.4

Principal exclusion criteria

1.Patients with poorly differentiated neuroendocrine carcinoma, high-grade neuroendocrine carcinoma, adenocarcinoid, pancreatic islet cell carcinoma, gastrinoma, goblet cell carcinoid, and small cell carcinoma.
2.Patients with pancreat NET or NET of origins other than GI or lung
3.Patients with history of or active symptoms of carcinoid syndrome (e.g. flushing, diarrhea).
4.Prior systemic cytotoxic chemotherapy or targeted therapy.
6.Hepatic intra-arterial embolization within the last 6 months (or 1 month if there is measurable disease in other organs besides the liver)
7.Prior therapy with mTOR inhibitors (e.g. sirolimus, temsirolimus, deforolimus).
8.Known intolerance or hypersensitivity to everolimus or other rapamycins (e.g. sirolimus, temsirolimus).
9.Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral everolimus.
10.Uncontrolled diabetes mellitus.
11.Patients who have any severe and/or uncontrolled medical conditions such as:
•unstable angina pectoris, symptomatic congestive heart failure, myocardial infarction ≤6 months prior to randomization, serious uncontrolled cardiac arrhythmia;
•active or uncontrolled severe infection;
•liver disease such as cirrhosis, decompensated liver disease, and chronic hepatitis (i.e. quantifiable HBV-DNA and/or positive HbsAg, quantifiable HCV-RNA).
12.Chronic treatment with corticosteroids or other immunosuppressive agents.
13.Known history of HIV seropositivity.
14.Pregnant or nursing (lactating) women, where pregnancy is defined
as the state of a female after conception and until the termination of
gestation, confirmed by a positive hCG laboratory test
Other protocol-defined exclusion criteria may apply

1. Patienten met een slecht gedifferentieerde neuro endocrien carcinoom, hoge graad neuroendrocrien carcinoom, adenocarcinoid, pancreatisch eiland cel carcinoom, insulinoom, glucagonoom, gastrinoom, goblet cel carcinoid, grootcellig neuroendrocrien carcinoom en kleincellig carcinoom
2 patienten met pancreas NET of NET welke niet ontstaan zijn uit maag-darm of long
3. patienten met een geschiedenis van of huidige actieve symptomen van carcinoid syndrome
4. meer dan 1 lijn chemotherapie
5. eerdere behandeling met targeted therapie
6. hepatische intraartieriele embolisatie in de voorgaande 6 maanden. Cryoablatie or RFA van hepatische metastasen binnen 2 maanden van randomisatie
7. eerdere therapie met mTOR remmers
8. Bekende intolerantie or overgevoeligheid voor everolimus of andere rapamycine analogen
9. bekende verminderde GI functie of GI stoornis waardoor de absorptie van orale everolimus significant verminderd wordt.
10. ongecontroleerde diabetes mellitus gedefineerd als HbA1c >8% ondanks therapie
11. Patienten met ongecontroleerde medische condities als
a) angina pectoris, symptomatische congestief hartfalen, myocard infarct ≤6 maanden voor randomisatie, ongecontrolleerde cardiac arrhythmia
b) actieve of ongecontroleerde forse infectie
c) lever ziekte als cirhose, chronische hepatitis,
d) bekende verminderde longfunctie
e) actieve, bloedende diathesis
12. chronische behandeling met corticosteroiden of andere immuunonderdrukkers
13 bekend HIV seropositief
14 zwanger of borstvoedende vrouwen, waarbij zwangerschap de staat is van een vrouw na conceptie en het uitblijven van menstruatie, bevestigd door een positieve hCG lab test.

E.5 End points

E.5.1

Primary end point(s)

Tumor assesments as per modified RECIST 1.0 based on local assessment. Progression free survival (PFS)

tumor evaluatie op basis van RECIST 1.0 gebaseerd op locale metingen. Progression free survival (PFS)

E.5.1.1

Timepoint(s) of evaluation of this end point

Every 12 weeks until disease progression, start of futher anti-tumor therapy or intolerable toxicity, whichever comes first.

Elke 12 weken tot aan ziekte progressie, start van andere anti-tumor therapie of onacceptablele toxiciteit.

E.5.2

Secondary end point(s)

1. Overall Survival (OS).
2. Safety evaluation and efficacy in everolimus.
3. FACT-G total score over time.
4. Objective response rate (ORR).
5. Changes from baseline in Chromogranin A (CgA) and Neuron specific enolase (NSE) levels.
6. Pre-dose concentration (Cmin)

1. Algehele Overleving (OS)
2. veiligheid en efficiteit van everolimus
3. FACT-G totaal score
4. Objectieve response waarde (ORR)
5. verandering in baseline Chromogranin A (CgA) en Neuron specific enolase (NSE) niveau
6. Pre-dose concentratie (Cmin)

E.5.2.1

Timepoint(s) of evaluation of this end point

1. Continuously during the treatment period. Every 12 weeks during follow-up.
2. Continuously
3. Every 12 weeks until start of futher anti-tumor therapy.
4. Every 12 weeks until disease progression, start of futher anti-tumor. therapy or intolerable toxicity, whichever comes first.
5. Every visit until end of treatment.
6. cycle 2 (day 29)

1. continue gedurende de behandel periode. Elke 12 weken tijdens de follow-up
2. continue
3. elke 12 weken tot aan de start van een volgende anti-tumor therapie
4. Elke 12 weken tot aan ziekte progressie, start van een volgende anti-tumor therapie of niet acceptabele toxiciteit.
5. elke visite tot aan einde van de behandeling
6. kuur 2 (dag 29)

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

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

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

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

Yes

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

Austria

Belgium

Canada

China

Colombia

Czech Republic

Egypt

Germany

Greece

Hungary

Italy

Japan

Korea, Republic of

Lebanon

Netherlands

Norway

Peru

Poland

Russian Federation

Saudi Arabia

Slovakia

South Africa

Spain

Taiwan

Thailand

Turkey

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

All patients will be treated until disease progression, unacceptable toxicity, patient withdrawal, or discontinuation for any other reason.

Alle patienten zullen worden behandelig tot aan ziekte progressie, onacceptabele toxiciteit, terugtrekken van een patient of beeindiging om elke andere reden

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:

190

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

135

F.4.2.2

In the whole clinical trial

185

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)

As per local practice

volgens lokale Routine

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

2012-03-26

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2012-05-14

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2020-08-07

Select Country:	Select Age Range:
Select Trial Status:	Select Trial Phase:
Select Gender:
Select Date Range: to
Select Rare Disease:
IMP with orphan designation in the indication
Orphan Designation Number:
Results Status:
Clear advanced search filters

Austria
Belgium
Bulgaria
Croatia
Cyprus
Czechia
Denmark
Estonia
Finland
France
Germany
Greece
Hungary
Iceland
Ireland
Italy
Latvia
Liechtenstein
Lithuania
Luxembourg
Malta
Netherlands
Norway
Poland
Portugal
Romania
Slovakia
Slovenia
Spain
Sweden
United Kingdom
Outside EU/EEA

Clinical trials