title: A randomized phase 3 study on the optimization of the combination of bevacizumab with FOLFOX/OXXEL in the treatment of patients with metastatic colorectal cancer-OBELICS (Optimization of BEvacizumab scheduLIng within Chemotherapy Scheme).
abstract: BACKGROUND
  Despite the improvements in diagnosis and treatment, colorectal cancer (CRC) is the second cause of cancer deaths in both sexes. Therefore, research in this field remains of great interest. The approval of bevacizumab, a humanized anti-vascular endothelial growth factor (VEGF) monoclonal antibody, in combination with a fluoropyrimidine-based chemotherapy in the treatment of metastatic CRC has changed the oncology practice in this disease. However, the efficacy of bevacizumab-based treatment, has thus far been rather modest. Efforts are ongoing to understand the better way to combine bevacizumab and chemotherapy, and to identify valid predictive biomarkers of benefit to avoid unnecessary and costly therapy to nonresponder patients. The BRANCH study in high-risk locally advanced rectal cancer patients showed that varying bevacizumab schedule may impact on the feasibility and efficacy of chemo-radiotherapy.
  
  
  METHODS
  OBELICS is a multicentre, open-label, randomised phase 3 trial comparing in mCRC patients two treatment arms (1:1): standard concomitant administration of bevacizumab with chemotherapy (mFOLFOX/OXXEL regimen) vs experimental sequential bevacizumab given 4 days before chemotherapy, as first or second treatment line. Primary end point is the objective response rate (ORR) measured according to RECIST criteria. A sample size of 230 patients was calculated allowing reliable assessment in all plausible first-second line case-mix conditions, with a 80% statistical power and 2-sided alpha error of 0.05. Secondary endpoints are progression free-survival (PFS), overall survival (OS), toxicity and quality of life. The evaluation of the potential predictive role of several circulating biomarkers (circulating endothelial cells and progenitors, VEGF and VEGF-R SNPs, cytokines, microRNAs, free circulating DNA) as well as the value of the early [(18)F]-Fluorodeoxyglucose positron emission tomography (FDG-PET) response, are the objectives of the traslational project.
  
  
  CONCLUSIONS
  Overall this study could optimize bevacizumab scheduling in combination with chemotherapy in mCRC patients. Moreover, correlative studies could improve the knowledge of the mechanisms by which bevacizumab enhance chemotherapy effect and could identify early predictors of response. EudraCT Number: 2011-004997-27 TRIAL REGISTRATION: ClinicalTrials.gove number, NCT01718873.
authors: Multidisciplinary Treatment Unit, Gastrointestinal Medical Oncology Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione Giovanni Pascale" - IRCCS, Napoli, Italy. a.avallone@istitutotumori.na.it.|Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione Giovanni Pascale" - IRCCS, Napoli, Italy. a.avallone@istitutotumori.na.it.
authors: Antonio
authors: A
authors: Avallone
authors: Clinical Trials Unit, Istituto Nazionale Tumori "Fondazione G. Pascale" - IRCCS, Napoli, Italy. m.piccirillo@istitutotumori.na.it.
authors: Maria Carmela
authors: MC
authors: Piccirillo
authors: Nuclear Medicine Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione Giovanni Pascale" - IRCCS, Napoli, Italy. l.aloj@istitutotumori.na.it.
authors: Luigi
authors: L
authors: Aloj
authors: Gastrointestinal Medical Oncology Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione Giovanni Pascale" - IRCCS, Napoli, Italy. g.nasti@istitutotumori.na.it.
authors: Guglielmo
authors: G
authors: Nasti
authors: Colorectal Surgery Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione Giovanni Pascale" - IRCCS, Napoli, Italy. p.delrio@istitutotumori.na.it.
authors: Paolo
authors: P
authors: Delrio
authors: Hepatobiliary Surgery Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione Giovanni Pascale" - IRCCS, Napoli, Italy. f.izzo@istitutotumori.na.it.
authors: Francesco
authors: F
authors: Izzo
authors: Experimental Pharmacology Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione Giovanni Pascale" - IRCCS, Napoli, Italy. e.digennaro@istitutotumori.na.it.
authors: Elena
authors: E
authors: Di Gennaro
authors: Pathology Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione Giovanni Pascale" - IRCCS, Napoli, Italy. f.tatangelo@istitutotumori.na.it.
authors: Fabiana
authors: F
authors: Tatangelo
authors: Radiology Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione Giovanni Pascale" - IRCCS, Napoli, Italy. v.granata@istitutotumori.na.it.
authors: Vincenza
authors: V
authors: Granata
authors: Laboratory Medicine Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione Giovanni Pascale" - IRCCS, Napoli, Italy. e.cavalcanti@istitutotumori.na.it.
authors: Ernesta
authors: E
authors: Cavalcanti
authors: Pharmacy Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione Giovanni Pascale" - IRCCS, Napoli, Italy. p.maiolino@istitutotumori.na.it.
authors: Piera
authors: P
authors: Maiolino
authors: Gastrointestinal Surgery Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione Giovanni Pascale" - IRCCS, Napoli, Italy. f.bianco@istitutotumori.na.it.
authors: Francesco
authors: F
authors: Bianco
authors: Vascular Access Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione Giovanni Pascale" - IRCCS, Napoli, Italy. p.aprea@istitutotumori.na.it.
authors: Pasquale
authors: P
authors: Aprea
authors: Endoscopy Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione Giovanni Pascale" - IRCCS, Napoli, Italy. m.debellis@istitutotumori.na.it.
authors: Mario
authors: M
authors: De Bellis
authors: Radiotherapy Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione Giovanni Pascale" - IRCCS, Napoli, Italy. b.pecori@istitutotumori.na.it.
authors: Biagio
authors: B
authors: Pecori
authors: Medical Oncology Unit, San Carlo Hospital, Potenza, Italy. oncogerry@yahoo.it.
authors: Gerardo
authors: G
authors: Rosati
authors: Department of Clinical Medicine and Surgery, University Federico II, Naples, Italy. chiara.carlomagno@unina.it.
authors: Chiara
authors: C
authors: Carlomagno
authors: A.O. Valtellina e Valchiavenna, Sondrio, Italy. alessandro.bertolini@aovv.it.
authors: Alessandro
authors: A
authors: Bertolini
authors: Medical Statistics Unit, Second University, Naples, Italy. ciro.gallo@unina2.it.
authors: Ciro
authors: C
authors: Gallo
authors: Gastrointestinal Medical Oncology Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione Giovanni Pascale" - IRCCS, Napoli, Italy. c.romano@istitutotumori.na.it.
authors: Carmela
authors: C
authors: Romano
authors: Experimental Pharmacology Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione Giovanni Pascale" - IRCCS, Napoli, Italy. a.leone@istitutotumori.na.it.
authors: Alessandra
authors: A
authors: Leone
authors: Nuclear Medicine Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione Giovanni Pascale" - IRCCS, Napoli, Italy. corradina.caraco@istitutotumori.na.it.
authors: Corradina
authors: C
authors: Caracò
authors: Radiology Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione Giovanni Pascale" - IRCCS, Napoli, Italy. e.delutiodicastelguidone@istitutotumori.na.it.
authors: Elisabetta
authors: E
authors: de Lutio di Castelguidone
authors: Clinical Trials Unit, Istituto Nazionale Tumori "Fondazione G. Pascale" - IRCCS, Napoli, Italy. g.daniele@istitutotumori.na.it.
authors: Gennaro
authors: G
authors: Daniele
authors: Radiology Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione Giovanni Pascale" - IRCCS, Napoli, Italy. o.catalano@istitutotumori.na.it.
authors: Orlando
authors: O
authors: Catalano
authors: Pathology Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione Giovanni Pascale" - IRCCS, Napoli, Italy. g.botti@istitutotumori.na.it.
authors: Gerardo
authors: G
authors: Botti
authors: Radiology Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione Giovanni Pascale" - IRCCS, Napoli, Italy. a.petrillo@istitutotumori.na.it.
authors: Antonella
authors: A
authors: Petrillo
authors: Gastrointestinal Surgery Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione Giovanni Pascale" - IRCCS, Napoli, Italy. g.romano@istitutotumori.na.it.
authors: Giovanni M
authors: GM
authors: Romano
authors: Gastrointestinal Medical Oncology Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione Giovanni Pascale" - IRCCS, Napoli, Italy. r.iaffaioli@istitutotumori.na.it.
authors: Vincenzo R
authors: VR
authors: Iaffaioli
authors: Nuclear Medicine Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione Giovanni Pascale" - IRCCS, Napoli, Italy. s.lastoria@istitutotumori.na.it.
authors: Secondo
authors: S
authors: Lastoria
authors: Clinical Trials Unit, Istituto Nazionale Tumori "Fondazione G. Pascale" - IRCCS, Napoli, Italy. f.perrone@istitutotumori.na.it.
authors: Francesco
authors: F
authors: Perrone
authors: Experimental Pharmacology Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione Giovanni Pascale" - IRCCS, Napoli, Italy. a.budillon@istitutotumori.na.it.
authors: Alfredo
authors: A
authors: Budillon
mesh_terms: D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000009:adverse effects; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects; D000068258:Bevacizumab / Q000008:administration & dosage* / Q000009:adverse effects; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D018572:Disease-Free Survival; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D002955:Leucovorin / Q000008:administration & dosage; D008297:Male; D008875:Middle Aged; D009944:Organoplatinum Compounds / Q000008:administration & dosage; D011379:Prognosis; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D009944:Organoplatinum Compounds; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab; D002955:Leucovorin; D005472:Fluorouracil