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

Study Overview

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

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.

N/A

Neuroendocrine Carcinomas

DRUG: Folfiri-bevacizumab
DRUG: Folfiri

69HCL14_0442
2016-001305-16 (EUDRACT_NUMBER Identifier) (EUDRACT_NUMBER: )

Study Record Dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Registration Dates	Results Reporting Dates	Study Record Updates
First Submitted 2016-06-29	Results First Submitted N/A	Last Update Submitted that met QC Criteria 2025-08-26
First Submitted that Met QC Criteria 2016-06-29	Results First Submitted that Met QC Criteria N/A	Last Update Posted (ESTIMATED) 2025-09-03
First Posted (ESTIMATED) 2016-07-01	Results First Posted N/A	Last Verified 2025-08

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

Design Details

Primary Purpose:
Treatment

Allocation:
Randomized

Interventional Model:
Parallel

Masking:
None

Arms and Interventions

Participant Group/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-bevacizumab Patient treated with a combination Folfiri-bevacizumab. Treatment every 2 weeks (D1 = D15) DRUG: Folfiri Patient treated with Folfiri only. Treatment every 2 weeks (D1 = D15)

Participant Group/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-bevacizumab

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

DRUG: Folfiri

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

Primary Outcome Measures	Measure Description	Time Frame
Proportion of patients alive	The primary endpoint is the proportion of patients alive 6 months after treatment	6 months after treatment

Secondary Outcome Measures	Measure Description	Time Frame

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person’s general health condition or prior treatments.

Ages Eligible for Study:
ALL

Sexes Eligible for Study:
18 Years

Accepts Healthy Volunteers:

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.

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, 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 (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, 3. 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.

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Publications

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Walter T, Lievre A, Coriat R, Malka D, Elhajbi F, Di Fiore F, Hentic O, Smith D, Hautefeuille V, Roquin G, Perrier M, Dahan L, Granger V, Sobhani I, Mineur L, Niccoli P, Assenat E, Scoazec JY, Le Malicot K, Lepage C, Lombard-Bohas C. Bevacizumab plus FOLFIRI after failure of platinum-etoposide first-line chemotherapy in patients with advanced neuroendocrine carcinoma (PRODIGE 41-BEVANEC): a randomised, multicentre, non-comparative, open-label, phase 2 trial. Lancet Oncol. 2023 Mar;24(3):297-306. doi: 10.1016/S1470-2045(23)00001-3. Epub 2023 Feb 2.

Learn

Resources

PatientS

Caregivers

Clinical Trial Record