Clinical Trials Register

Summary
EudraCT Number:	2016-001305-16
Sponsor's Protocol Code Number:	69HCL14_0442
National Competent Authority:	France - ANSM
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2017-07-06
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

France - ANSM

A.2

EudraCT number

2016-001305-16

A.3

Full title of the trial

Assessment of the efficacy of bevacizumab in combination with Folfiri as second-line treatment after the failure of the cisplatin (or carboplatin)-etoposide combination in patients suffering from an advanced inoperable poorly differentiated neuroendocrine carcinoma of an unknown or gastroentero-pancreatic primary cancer. A phase 2 non-comparative randomized study. PRODIGE 41 - BEVANEC study

Evaluation de l’efficacité du bevacizumab associé à du Folfiri en deuxième ligne après échec de l’association cisplatine (ou carboplatine) – étoposide chez des patients atteints d’un carcinome neuroendocrine peu différencié avancé inopérable. Etude de phase 2 randomisée non comparative. Etude Prodige 41 - BEVANEC

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

BEVANEC

A.4.1

Sponsor's protocol code number

69HCL14_0442

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	Hospices Civils de Lyon - Direction de la Recherche Clinique et de l'Innovation
B.1.3.4	Country	France
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	Minsitère de la Santé
B.4.2	Country	France
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Hospices Civils de Lyon - Direction de la Recherche Clinique et de l'Innovation
B.5.2	Functional name of contact point	Catherine CERESER
B.5.3	Address:
B.5.3.1	Street Address	3 quai des Célestins
B.5.3.2	Town/ city	Lyon cedex 2
B.5.3.3	Post code	69229
B.5.3.4	Country	France
B.5.4	Telephone number	472 40 68 93+33
B.5.5	Fax number	472 11 51 90+33
B.5.6	E-mail	drci_promo@chu-lyon.fr

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	AVASTIN 25 mg/ml
D.2.1.1.2	Name of the Marketing Authorisation holder	Roche
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.3.4	Pharmaceutical form	Concentrate for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	BEVACIZUMAB
D.3.9.1	CAS number	216974-75-3
D.3.9.4	EV Substance Code	SUB16402MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	25
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	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	Yes
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

Neuroendocrine carcinoma

E.1.1.1

Medical condition in easily understood language

Neuroendocrine carcinoma

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	10057270
E.1.2	Term	Neuroendocrine 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

Show that, after the failure of a first-line chemotherapy using platinum-etoposide, the combination Folfiri-bevacizumab allows significant prolongation of overall survival in adult patients with GEP-NEC

E.2.2

Secondary objectives of the trial

- Objective response rate (complete response + partial response),
- Response duration
- Disease control rate (objective response + stable disease),
- Progression-free survival,
- Tolerance,
- Biochemical response (LDH, NSE, chromogranin A)

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

- Man or woman aged ≥ 18 years old,
- Poorly differentiated neuroendocrine carcinoma (NEC) from a gastroentero-pancreatic (GEP) primary or an unknown primary cancer, locally advanced and/or metastatic (according to the WHO 2010),
- Centralized review of the diagnostic by a consulting pathologist specializing in NET (TENPATH network),
- Recommendation of a second-line chemotherapy after progression documented using the RECIST criteria v.1.1 and after a first-line chemotherapy treatment by cisplatin (or carboplatin) + etoposide or in the case of progression in the 6 months following the discontinuation of this first-line treatment,
- Patients presenting at least one measurable target lesion according to the RECIST criteria v.1.1, in an area not previously irradiated,
- General condition inferior or equal 2 (WHO),
- Patient who signed the informed consent form.

E.4

Principal exclusion criteria

1) Relating to the tumor, the patient and the previous treatment:
- Well differentiated gastroentero-pancreatic neuroendocrine tumor (NET G1 and G2 according to the WHO 2010),
- Mixed tumor,
- First-line chemotherapy other than cisplatin (carboplatin) and etoposide,
- All malignant disease in the three year before randomization, with the exception of basal cell carcinoma or in situ cervical cancer treated for curative purposes,
- A pregnant or breastfeeding woman,
- Lack of efficient contraception (for men or women of reproductive age),
- All medical, geographical, social, and psychological conditions or a legal situation that will not allow the patient to finish the study or sign an informed consent form.

2) Relating to the chemotherapy (Folfiri):
- Any of the following uncontrolled progressive diseases in the 6 months before randomization: liver failure, renal insufficiency, respiratory distress, congestive heart failure (NYHA III-IV), unstable angina, myocardial infarction, significant arrhythmia,
- Known deficiency in dihydropyrimidine dehydrogenase,
- Known Gilbert's syndrome,
- Total bilirubin level >1.5x the upper limit of normal (ULN); AST and/or ALT >5x ULN; TP <50%;
- Neutrophils <1.5x109/l, platelets <100x109/l, hemoglobin <10 g/dl,
- Chronic uncontrolled diarrhea, unresolved intestinal occlusion or subocclusion,
- History of anaphylactic reaction or known intolerance to atropine (sulfate) or to loperamide or to antiemetics administered in association with Folfiri.

3) Relating to bevacizumab:
- Uncontrolled wound and important surgery within the last 28 days
- Uncontrolled brain metastases (by local treatment),
- All uncontrolled progressive disease within 1 month prior to randomization: grade 3-4 gastrointestinal bleeding (peptic ulcer, erosive esophagitis or gastritis), infectious disease or intestinal inflammation, diverticulitis, pulmonary embolism or other uncontrolled thromboembolic event,
- Uncontrolled high blood pressure, defined as a systolic blood pressure >140 mmHg or diastolic pressure >90 mmHg,
- Patients receiving anticoagulant treatment with an unstable dose of a vitamin K antagonist treatment, and/or having an abnormal INR (>3) in the four weeks before the randomization,
- Verified proteinuria above or equal to 1g/24 hours measured from 24 hours of urine if the urinary protein dipstick control is above or equal to 2+,
- Creatinine clearance (MDRD) <50 ml/min.
- Hypersensitivity to the active substance or to any of the excipients.
- Hypersensitivity to Chinese Hamster Ovary (CHO) cell products or other recombinant human or humanised antibodies.

E.5 End points

E.5.1

Primary end point(s)

Proportion of patients alive 6 months after the beginning of treatment

E.5.1.1

Timepoint(s) of evaluation of this end point

6 months after beginning of treatment

E.5.2

Secondary end point(s)

- The objective response is measured every 8 weeks by morphological examination (MRI or thoracic-abdominal-pelvic and cerebral CT scans) based the RECIST criteria v.1.1
- The response duration is calculated from the first objective response until progression or death
- Disease control rate is the sum of objective response rate (complete response rate + partial response rate) and stable disease
- Progression-free survival is calculated from the 1st administration of the treatment until progression, as defined by the RECIST criteria v.1.1
- The toxicity of the treatments is measured by the frequency and the severity of the adverse events, serious or not, at each official patient visit and at each post treatment follow-up visit using the CTCAE Version 4.03 depending on the actual treatment received (with or without bevacizumab).
- The best biochemical response on each marker (LDH, NSE and CgA) is calculated between the start of the treatment and the lowest level occurring during chemotherapy. Biochemical response is defined as the normalization or the decrease of the levels by more than 50% compared to pre-treatment values.

E.5.2.1

Timepoint(s) of evaluation of this end point

Every 8 weeks

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)

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

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

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)

Yes

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

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

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

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:

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

124

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)

None

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

2017-07-05

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2017-05-11

P. End of Trial
P.	End of Trial Status	Ongoing

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