BEVANEC: Assessment of the Efficacy of Bevacizumab in Combination With Folfiri as Second-line Treatment in Patients Suffering From an Advanced Inoperable Poorly Differentiated Neuroendocrine Carcinoma of an Unknown or Gastroentero-pancreatic Primary Cancer

Sponsor

Hospices Civils de Lyon (Other)

Overall Status

Recruiting

CT.gov ID

NCT02820857

Collaborator

(none)

145

Enrollment

Locations

Arms

Anticipated Duration (Months)

5.4

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Poorly differentiated neuroendocrine carcinomas (NEC) are a sub-group of aggressive neuroendocrine neoplasms (NEN). The most common primary sites are broncho-pulmonary and digestive. The gastroentero-pancreatic NECs (GEP-NEC) represent 7-21% of all of the NENs.

Recent data on the initial presentation of GEP-NEC have been reported in two retrospective studies and a French cohort study. No standard second-line treatment has been defined for NECs. Despite a very negative prognosis, these NECs have a certain amount of chemosensitivity, close to that of bronchial NECs. Multiple-drug therapies such as Folfiri, or Folfox, or single drug treatments such as temozolomide are the proposed options but with a low level of proof Bevacizumab associated with a cytotoxic chemotherapy has shown promising results in well differentiated neuroendocrine tumors (NET), known for being hypervascular. The efficacy of bevacizumab has also been suggested in patients with NEC, but never in the context of a phase II study. Its combination with Folfiri is efficient and well tolerated in metastatic colorectal cancer. The combination Folfiri-bevacizumab potentially represents an optimized treatment compared to chemotherapy with only Folfiri. No phase II or III studies have reported results for these patients, and no on-going phase II or III trial have been identified to date.

The main objective of this study is to 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.

Condition or Disease	Intervention/Treatment	Phase
Neuroendocrine Carcinomas	Drug: Folfiri-bevacizumab Drug: Folfiri	Phase 2

Study Design

Study Type:

Interventional

Anticipated Enrollment :

145 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Sep 4, 2017

Anticipated Primary Completion Date :

Mar 4, 2023

Anticipated Study Completion Date :

Sep 4, 2024

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Folfiri-bevacizumab Patient treated with a combination Folfiri-bevacizumab. Treatment every 2 weeks (D1 = D15)	Drug: Folfiri-bevacizumab Patient treated with a combination Folfiri-bevacizumab. Treatment every 2 weeks (D1 = D15)
Active Comparator: Folfiri Patient treated with Folfiri only. Treatment every 2 weeks (D1 = D15)	Drug: Folfiri Patient treated with Folfiri only. Treatment every 2 weeks (D1 = D15)

Arm

Intervention/Treatment

Experimental: Folfiri-bevacizumab

Patient treated with a combination Folfiri-bevacizumab. Treatment every 2 weeks (D1 = D15)

Drug: Folfiri-bevacizumab

Patient treated with a combination Folfiri-bevacizumab. Treatment every 2 weeks (D1 = D15)

Active Comparator: Folfiri

Patient treated with Folfiri only. Treatment every 2 weeks (D1 = D15)

Drug: Folfiri

Patient treated with Folfiri only. Treatment every 2 weeks (D1 = D15)

Outcome Measures

Primary Outcome Measures

Proportion of patients alive [6 months after treatment]
The primary endpoint is the proportion of patients alive 6 months after treatment

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Man or woman aged ≥ 18 years old,
Poorly differentiated neuroendocrine carcinoma (NEC) from a gastrointestinal tract (from esophagus to anal canal) and biliopancreatic primary or an unknown primary cancer, locally advanced and/or metastatic,
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 event of progression in the 6 months following the discontinuation of this first-line treatment,
Recommendation of a second-line chemotherapy for the refractory patient or contraindicated for platinum-etoposide chemotherapy
Patients presenting at least one measurable target lesion according to the RECIST criteria v.1.1, in an area not previously irradiated,
General condition ≤ 2 (WHO),
Patient of child bearing age accepting to use an effective contraception during treatment and until 6 months after the last administration,
Patient who signed the informed consent form.

Exclusion Criteria:

Relating to the tumor, the patient, and previous treatment:

Well differentiated neuroendocrine tumor
Mixed tumor, except if the NEC component is > 70%, the patient is eligible,
First-line chemotherapy other than cisplatin (or carboplatin) and etoposide,
All malignant disease in the three years before randomization, with the exception of basal cell carcinoma or in situ 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,

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 (Aspartate transaminase) and/or ALT (Alanine transaminase) >5x ULN; TP <50%;
Neutrophils <1.5x109/l, platelets <100x109/l, hemoglobin <9 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,
All treatment with concomitant anticonvulsive agents, CYP3A4 inducers (phenytoin, phenobarbital, carbamazepine), discontinued for at least 7 days,

Relating to bevacizumab:

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.

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	Service d'Hépato-Gastroenterologie et Oncologie Digestive, Hôpital Sud, CHU d'Amiens	Amiens	France	80054
2	Service d'Hépatogastroentérologie, CHU d'Angers	Angers	France	49933
3	Service d'Oncologie et Radiothérapie, Institut Sainte Catherine	Avignon	France	84918
4	Service de Gastroentérologie et Oncologie Digestive, Hôpital Avicenne	Bobigny	France	93000
5	Service de Gastroentérologie et Pancréatologie, Hôpital Beaujon, APHP	Clichy	France	92118
6	Service de Gastroentérologie, CHU Henri Mondor	Créteil	France	94000
7	Service d'Hépato-Gastroentérologie et Oncologie Digestive, CHU de Dijon	Dijon	France	21000
8	Service d'Hépatogastroentéologie, Hôpital Michallon, CHU de Grenoble	Grenoble	France	38043
9	Département de Cancérologie Urologique et Digestive, Centre Oscar Lambret	Lille	France	59020
10	Département de cancérologie médicale - Groupe des tumeurs endocrines, Centre Léon Bérard	Lyon	France	69008
11	Service d'Oncologie Médicale - Hôpital Edouard Herriot - Hospices Civils de Lyon	Lyon	France	69437
12	Département d'Oncologie Médicale, Institut Paoli Calmettes	Marseille	France	13009
13	Service d'Hépato-Gastroentérologie et d'Oncologie Digestive, Hôpital de la Timone, APHM	Marseille	France	13365
14	Service d'Oncologie Médicale, Hôpital Saint Eloi, CHU de Montpellier	Montpellier	France	34298
15	Service d'Hépatogastroentérologie, CHR d'Orléans	Orléans	France	45067
16	Département d'Oncologie Médicale, Hôpital Saint-Antoine	Paris	France	75012
17	Service d'Hépato-Gastroentérologie et d'Oncologie Digestive, Hôpital de la Salpêtrière, APHP	Paris	France	75013
18	Service de Gastroentérologie, Hôpital Cochin, APHP	Paris	France	75014
19	Service d'Hépato-Gastroenterologie et Oncologie Digestive, Hôpital Européen Georges Pompidou, APHP	Paris	France	75015
20	Service d'Hépato-Gastroentérologie et d'Oncologie Digestive, Hôpital Haut Lévêque, CHU Bordeaux	Pessac	France	33604
21	Pôle Régional de Cancérologie, CHU de Poitiers	Poitiers	France	86021
22	Service d'Hépato-Gastroentérologie et Cancérologie, Hôpital Robert Debré, CHU de Reims	Reims	France	51100
23	Service d'Hépatogastroentérologie, Hôpital Pontchaillou, CHU de Rennes	Rennes	France	35000
24	Service de Gastroentérologie, CHU de Rouen	Rouen	France	76031
25	Service de Gastro-Entérologie, Hôpital Nord, CHU de ST-Etienne	Saint-Priest-en-Jarez	France	42270
26	Service d'Oncologie Médicale, Hôpital Civil, CHU de Strasbourg	Strasbourg	France	67200
27	Service d'Oncologie Endocrinienne, Institut Gustave Roussy	Villejuif	France	94805