Clinical Trials Register

Summary
EudraCT Number:	2011-002887-26
Sponsor's Protocol Code Number:	CRAD001T2302
National Competent Authority:	UK - MHRA
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2012-02-29
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

UK - MHRA

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

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

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 Pharmaceuticals UK Ltd
B.5.2	Functional name of contact point	Medical Information Services
B.5.3	Address:
B.5.3.1	Street Address	Frimley Business Park, Frimley
B.5.3.2	Town/ city	Camberley, Surrey
B.5.3.3	Post code	GU16 7SR
B.5.3.4	Country	United Kingdom
B.5.4	Telephone number	4412768370
B.5.5	Fax number	4412768449
B.5.6	E-mail	medinfo.uk@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

E.1.1.1

Medical condition in easily understood language

Advanced neuroendocrine cancer of gastrointestinal or lung origin

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	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

E.2.2

Secondary objectives of the trial

- To compare overall survival (OS) between study arms
- To determine the safety and tolerability of everolimus in this
patient population
- To evaluate overall response rate (ORR) and Disease Control
Rate (DCR) in the 2 study arms
- To compare the HRQoL based on the FACT-G total score
between study arms
- To compare changes from baseline in Chromogranin A (CgA)
and Neuron specific enolase (NSE) levels between study arms
- To compare time to deterioration for WHO performance status
between study arms
- To determine the exposure of everolimus at the steady-state
pre-dose concentration (Cmin) at Cycle 2 (Day 29)

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

E.4

Principal exclusion criteria

1.Patients with poorly differentiated neuroendocrine carcinoma, highgrade
neuroendocrine carcinoma, adenocarcinoid, pancreatic islet cell
carcinoma, gastrinoma, goblet cell carcinoid, and small cell carcinoma.
2.Patients with pancreatic 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.More than one prior line of chemotherapy;
5. Prior 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

E.5 End points

E.5.1

Primary end point(s)

PFS per modified RECIST 1.0 assessed by central
radiological assessment

E.5.1.1

Timepoint(s) of evaluation of this end point

From date of randomization to progression or death.

E.5.2

Secondary end point(s)

1. Overall Survival (OS).
2. Safety evaluation and tolerability of everolimus.
3. Objective response rate (ORR) and Disease control rate (DCR).
4. FACT-G total score over time.
5. Changes from baseline in Chromogranin A (CgA) and Neuron specific
enolase (NSE) levels.
6. time to deterioration for WHO performance status
7. Pre-dose concentration (Cmin)

E.5.2.1

Timepoint(s) of evaluation of this end point

For 1. to 6. : Every visit up from randomization to 5 years
7. Visit 3 (cycle 2, study Day 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

Yes

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.

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:

200

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

102

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

165

F.4.2.2

In the whole clinical trial

302

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

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

2012-03-20

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2012-02-28

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

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