BEVANEC: FOLFIRI +/- BEVACIZUMAB

Hospices Civils de Lyon / Prodige

Thomas WALTER,  Mail Walter

•    Main objective: 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.
•    Secondary objectives
– 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).

A national, multicenter, open, randomized phase II non-comparative study assessing the tolerance and efficacy of the combination Folfiri-bevacizumab versus a Folfiri chemotherapy after the failure of platinum-etoposide in patients suffering from progressive NEC of unknown or GEP primary cancer.

•    Man or woman aged > 18 years old,
•    Poorly differentiated neuroendocrine carcinoma (NEC) from a 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 event 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 < 2 (WHO),
•    Patient who signed the informed consent form.

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

•    Well differentiated gastroentero-pancreatic (GEP) neuroendocrine tumor (NET) (G1 and G2 according to the WHO 2010),
•    Mixed tumor,
•    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 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,

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 <1.5×109/l, platelets <100×109/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.

124 patients, 25 inclus au 03/08/2018