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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 (BEVANEC)

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ClinicalTrials.gov Identifier: NCT02820857
Recruitment Status : Recruiting
First Posted : July 1, 2016
Last Update Posted : January 10, 2019
Sponsor:
Information provided by (Responsible Party):
Hospices Civils de Lyon

Tracking Information
First Submitted Date  ICMJE June 29, 2016
First Posted Date  ICMJE July 1, 2016
Last Update Posted Date January 10, 2019
Actual Study Start Date  ICMJE September 4, 2017
Estimated Primary Completion Date September 4, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: December 14, 2017)
Proportion of patients alive [ Time Frame: 6 months after treatment ]
The primary endpoint is the proportion of patients alive 6 months after treatment
Original Primary Outcome Measures  ICMJE
 (submitted: June 29, 2016)
Proportion of patients alive [ Time Frame: 6 months after treatment ]
Change History Complete list of historical versions of study NCT02820857 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE Not Provided
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE 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
Official Title  ICMJE 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
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.

Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Neuroendocrine Carcinomas
Intervention  ICMJE
  • 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)
Study Arms  ICMJE
  • Experimental: Folfiri-bevacizumab
    Patient treated with a combination Folfiri-bevacizumab. Treatment every 2 weeks (D1 = D15)
    Intervention: Drug: Folfiri-bevacizumab
  • Active Comparator: Folfiri
    Patient treated with Folfiri only. Treatment every 2 weeks (D1 = D15)
    Intervention: Drug: Folfiri
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: June 29, 2016)
124
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE March 4, 2022
Estimated Primary Completion Date September 4, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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:

  1. 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,
  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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Thomas WALTER, MD 4 72 11 73 98 ext +33 thomas.walter@chu-lyon.fr
Contact: Emilie PROME 4 72 11 62 03 ext +33 emilie.prome@chu-lyon.fr
Listed Location Countries  ICMJE France
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02820857
Other Study ID Numbers  ICMJE 69HCL14_0442
2016-001305-16 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Hospices Civils de Lyon
Study Sponsor  ICMJE Hospices Civils de Lyon
Collaborators  ICMJE Not Provided
Investigators  ICMJE Not Provided
PRS Account Hospices Civils de Lyon
Verification Date January 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP