Clinical Trials Register

Summary
EudraCT Number:	2012-004550-28
Sponsor's Protocol Code Number:	AIO-NET-0112
National Competent Authority:	Germany - BfArM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2014-10-14
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

Germany - BfArM

A.2

EudraCT number

2012-004550-28

A.3

Full title of the trial

EVINEC: Safety and Tolerability of Everolimus as second-line treatment in poorly differentiated neuroendocrine carcinoma / neuroendocrine carcinoma G3 according to WHO 2010 and neuroendocrine tumor G3 - an investigtor initiated Phase II study.

EVINEC: Sicherheit und Verträglichkeit von Everolimus in der Zweitlinientherapie bei schlecht differenziertem neuroendokrinen Karzinom / neuroendokrinem Karzinom G3 (WHO 2010) und neuroendokrinem Tumor G3 – eine Arzt-initiierte Phase II Studie.

A.3.1

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

A.3.2

Name or abbreviated title of the trial where available

EVINEC

A.4.1

Sponsor's protocol code number

AIO-NET-0112

A.5.4

Other Identifiers

Name:

Novartis-Nr:

Number:

CRAD001KDE55T

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	AIO-Studien-gGmbH
B.1.3.4	Country	Germany
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	AIO-Studien-gGmbH
B.4.2	Country	Germany
B.4.1	Name of organisation providing support	Novartis Pharma GmbH
B.4.2	Country	Germany
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	AIO-Studien-gGmbH
B.5.2	Functional name of contact point	Sponsor
B.5.3	Address:
B.5.3.1	Street Address	Kuno-Fischer-Straße 8
B.5.3.2	Town/ city	Berlin
B.5.3.3	Post code	14057
B.5.3.4	Country	Germany
B.5.4	Telephone number	+4930814534431
B.5.5	Fax number	+4930322932926
B.5.6	E-mail	info@aio-studien-ggmbh.de

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 2,5 mg
D.2.1.1.2	Name of the Marketing Authorisation holder	Novartis Pharma GmbH
D.2.1.2	Country which granted the Marketing Authorisation	Germany
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.3.9.1	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	equal
D.3.10.3	Concentration number	2,5
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	Yes
D.2.1.1.1	Trade name	Afinitor 5 mg
D.2.1.1.2	Name of the Marketing Authorisation holder	Novartis Pharma GmbH
D.2.1.2	Country which granted the Marketing Authorisation	Germany
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.3.9.1	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	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

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

• Poorly differentiated neuroendocrine carcinoma, neuroendocrine carcinoma G3 (NEC G3 according to WHO 2010) with primary tumor outside lung
• Well to moderately differentiated neuroendocrine carcinoma (NET G1/G2) that switched to G3 (confirmed by histology)
• Neuroendocrine tumor G3 (NET G3)

E.1.1.1

Medical condition in easily understood language

neuroendocrine cancer

E.1.1.2

Therapeutic area

Diseases [C] - Cancer [C04]

MedDRA Classification

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 tolerability and safety of everolimus in second-line treatment of poorly differentiated neuroendocrine carcinoma / neuroendocrine carcinoma G3 according to WHO 2010 and neuroendocrine tumors G3. Safety and tolerability of Everolimus can be inferred if type, frequency and seriousness of observed AEs is comparable to those determined in previous Everolimus trials in NET (Radiant-1,2 and 3).

E.2.2

Secondary objectives of the trial

•To estimate progression free survival (PFS)
•To estimate Objective Response Rate (ORR)
•To estimate Disease control rate (DCR)
•To estimate Duration of Response (DR) and Time to Progression (TTP)
•To estimate Overall Survival (OS)
•To evaluate Quality of Life
•To explore blood levels of tumor markers (chromogranin A & B, neuronspecific enolase, progastrin releasing peptide) as correlative tumor markers for clinical outcome in NET patients
•To explore expression of mTOR pathway components in tumor tissue (archive) in correlation to tumor response

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Signed written informed consent
2. Male or female ≥18 years of age
3. Patients with poorly differentiated neuroendocrine carcinoma, neuroendocrine carcinoma G3 (NEC – G3 according to WHO 2010) or well or moderately differentiated neuroendocrine carcinoma (NET – G1/ G2) that switched to G3 (confirmed by histology) or neuroendocrine tumor G3 (NET G3) and disease progression as measured by RECIST 1.1
4. Progression during or after treatment with first-line platin-based chemotherapy. In NET G3 that switched from NET G2 the line of therapy is determined from time of revised histology (confirming a G3 NEN)
5. Measurable disease according to RECIST 1.1
6. ECOG status 0-2 (Karnofsky Performance status ≥80%)
7. Women of child-bearing potential must have a negative pregnancy test
8. Laboratory requirements:
• Hematology
o Absolute neutrophil count ≥1.5x10^9/L
o Platelet count ≥100x10^9/L
o Leukocyte count ≥3.0x10^9/L
o Hemoglobin ≥9 g/dL or 5.59 mmol/l
• Hepatic Function
o Total bilirubin ≤1.5 time the upper limit normal (ULN)
o AST ≤3xULN in absence of liver metastases, or ≤5xULN in presence of liver metastases
o ALT ≤3xULN in absence of liver metastases, or ≤5xULN in presence of liver metastases
• Renal Function
o Creatinine clearance ≥50 mL/min according to Cockroft-Gault formula
• Metabolic Function
o Magnesium ≥ lower limit of normal
o Calcium ≥ lower limit of normal
o Others:
o CRP (PCT if CRP is elevated to exclude infection)
o negative urinary screening test for leucocytes and nitrite to exclude urinary tract infection (U - stix)

E.4

Principal exclusion criteria

1. Known or suspected allergy or hypersensitivity reaction to any of the components of study treatment or their exipients.
2. Previous therapy with mTOR inhibitor
3.Radiotherapy :
• Concurrent radiotherapy involving target lesions used for this study.
• Concurrent palliative radiation (but radiation for non-target lesions is allowed if other target lesions are available outside the involved field)
• previous pre-operative or post-operative radiotherapy within 3 months before study treatment
4. History of other malignant tumors within the last 5 years, except basal cell carcinoma or curatively excised cervical carcinoma in situ
5. Known brain metastases unless adequately treated (surgery or radiotherapy) with no evidence of progression and neurologically stable off anticonvulsants and steroids
6. Clinically significant cardiovascular disease (including myocardial infarction, unstable angina, symptomatic congestive heart failure, serious uncontrolled cardiac arrhythmia) ≤1year before enrolment
7. Inadequate pulmonary function according to the Investigator’s judgment, history of interstitial lung disease e.g. pneumonitis or pulmonary fibrosis or evidence of interstitial lung disease on baseline chest CT scan
8. Known active HBV, HCV or HIV infection
9. Serious concomitant disease or medical condition that in the judgment of the investigator renders the patient at high risk from treatment complication
10. Any systemic disease requiring oral intake of corticosteroids (except for replacement therapy of corticosteroids – hydrocortisone in case of adrenal or pituitary insufficiency)
11. Hearing loss ≥ Grade 3 (CTCAE v4.03) 12. Patient pregnant or breast feeding, or planning to become pregnant within 8 weeks after the end of treatment
13. Patient (male or female) is not willing to use highly effective methods of contraception (per institutional standard) during treatment and for 8 weeks (male or female) after the end of treatment.
14. Concurrent treatment with other experimental drugs or participation in another clinical trial with any investigational drug within 28 days prior to treatment start
15. Concurrent treatment with inhibitors (e.g. itraconazol, ketoconazol) and inducers (e.g. phenytoin, rifampicin) of CYP3A4 and/or the multidrug efflux pump P-glycoprotein (PgP).
16. Known drug abuse/alcohol abuse
17.Peripheral polyneuropathy ≥ Grade 2 (CTCAE v4.03)
18. Active chronic inflammatory bowel disease
19. Any condition which might interfere with study objectives (e.g. infections) or would limit the patient’s ability to complete the study in the opinion of the investigator
20. Patient who has be incarcerated or involuntarily institutionalized by court order or the authorities (AMG § 40, Abs. 1 No. 4).
21. Affected persons who might be dependent on the sponsor or the investigator

E.5 End points

E.5.1

Primary end point(s)

•Incidence of adverse events (AEs) overall and by severity, and serious adverse events (SAEs).

E.5.1.1

Timepoint(s) of evaluation of this end point

at study end: Q1/2018

E.5.2

Secondary end point(s)

•Progression free survival (PFS) as the length of time during and after the treatment of a disease, such as cancer, that a patient lives with the disease but it does not get worse as per local radiology assessment using RECIST 1.1.)
•Objective response rate defined as the rate of best overall response (CR+PR), determined by RECIST V 1.1.
•Disease control rate defined as the rate of best overall response and stable disease (CR+PR+SD), determined by RECIST V 1.1.
•Duration of response is defined as the time from onset of the first objective tumor response (CR/PR) to objective tumor progression or death from any cause. Time to progression (TTP) is the time from date of start of treatment to the date of event defined as the first documented progression due to underlying cancer.
•OS is defined as the time from date of randomization to the date of death from any cause. If a patient is not known to have died at the date of analysis cut-off, the OS will be censored at the last date of contact.
•Quality of life (HRQoL) will be evaluated using the EORTC QLQ-C30.
•Percentage of patients showing normalization or a decrease of chromogranin A & B, neuronspecific enolase, progastrin releasing peptide.
•To explore expression of mTOR pathway components in tumor tissue (archive) in correlation to tumor response

E.5.2.1

Timepoint(s) of evaluation of this end point

at study end: Q1/2018

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

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)

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

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 planned recruitment of 40 patients will be discontinued when tumor progression has been observed for 28 patients. Patients who are still receiving study treatment at this time can be further treated until progression or an unacceptable toxicity occurs, or for any other reason, which might end the treatment.
The final statistical analysis will be performed when the last patient has completed at least 3 months of follow-up / the first follow-up visit.

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

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.1.3

Elderly (>=65 years)

Yes

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.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)

at the discretion of the local investigator at the patients' site

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

2015-03-12

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2014-11-28

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

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