The samples concentrations expressed in pg/mL will be assessed in triplicate and the average values used for statistical analyses. per Ibuprofen piconol treatment). The significance will be verified with a two-tailed log-rank test with an alpha value of the I-type error of 5%. Time-to-outcome will be described by KaplanCMeier curves and prognostic factors studied through multivariable analyses based on the Cox model. Secondary objectives include Ibuprofen piconol safety, responses duration and progression-free survival. A translational research will be conducted to measure several angiogenic proteins in patients serum before starting the therapy in order to evidence any angiogenic factor patterns related to outcome. Discussion: We present a large, prospective, observational study aiming to answer two scientific questions: (1) outcome differences between second-line treatments with FOLFIRI/bevacizumab beyond progression FOLFIRI/aflibercept in mRAS mCRC patients, (2) angiogenic factors patterns that could associate with efficacy and help oncologists to apply best the therapeutic anti-angiogenic strategies. Trial registration: The ARBITRATION trial (version 0.0, 13 April 2020) has been registered into the clinicaltrials.gov registry on 20 May 2020 with identifier “type”:”clinical-trial”,”attrs”:”text”:”NCT04397601″,”term_id”:”NCT04397601″NCT04397601. aflibercept) after failure of the first-line chemotherapy in mRAS mCRC patients. The present study is the first observational, pragmatic, prospective study aimed to report outcomes of mCRC patients treated with FOLFIRI plus bevacizumab FOLFIRI plus aflibercept in second-line treatment of mRAS mCRC. Rationale for evaluating angiogenic factors Neoangiogenesis has a crucial role in tumour progression. Among many soluble factors involved in this process [including vascular Ibuprofen piconol endothelial growth factors (VEGFs), transforming growth factor- and angiopoietin-1 and -2, fibroblast growth factors (FGFs), placental growth factor (PlGF)], VEGF-A and its receptors have a pivotal role and are understood best.17,18 Blockage of VEGF-A is responsible for the anti-tumor effects of bevacizumab, which is a humanized IgG1 monoclonal antibody specifically sequestering the VEGF-A and, in turn, inhibiting its angiogenic effects into tumors.9,10 However, aflibercept, a recombinant fusion protein between the Fc portion of IgG1 and binding portions of VEGFR 1 and 2 (VEGF Receptors 1 and 2), is an anti-angiogenic agent targeting both VEGF-A and PlGF;19 the last has been implicated in promoting angiogenesis in later phases of tumor progression.18,20 Additionally, PlGF is one of the pivotal angiogenic factors implicated in resistance to bevacizumab.21C24 Thus, the aim of the ARBITRATION study will be to evaluate VEGF-A and PlGF levels in patients serum before starting second-line chemotherapy with bevacizumab or aflibercept in order to evidence any pattern related to response and/or prognosis. The hypothesis is that knowledge of relative levels of VEGF and PIGF Rabbit polyclonal to NFKBIE could direct the choice for the best anti-angiogenic drug in second-line treatment of mRAS mCRC patients. Methods and design ARBITRATION is an observational, prospective, no-profit, two-arm, open-label study, conducted under real-word conditions and designed to describe any risk of death differences among FOLFIRI/bevacizumab and FOLFIRI/aflibercept, two suitable options in second-line Ibuprofen piconol treatment of mRAS mCRC patients progressing at first-line chemotherapy based on fluoropyrimidines, oxaliplatin and bevacizumab. It will be conducted in an academic center (Istituto Nazionale Tumori di Napoli, IRCCS G. Pascale in Naples, Italy). The study includes a biomarker analysis (characterization of angiogenic factors before second-line treatment start). Objectives The primary objective is patients survival (overall survival; OS) according to the different schedules. Activity will be evaluated according to Response Evaluation Criteria In Solid Tumors (RECIST) criteria, version 1.1. Secondary objectives include: safety, responses duration, and progression-free survival (PFS). Toxicity will be graded according to the Common Terminology Criteria for Adverse Events the National Cancer Institute, version 4.0, 14 June 2010. Response duration is defined as the time elapsing from documentation of objective response (Complete Response [CR] or Partial Response [PR]) to tumor progression. PFS will be calculated from the treatment start until progression (according to RECIST), OS until death from any cause. Tertiary objective is the study of angiogenic biological markers (VEGF-A and PlGF) as predictors of outcome (see the Translational research section below). Intent-to-treat population and per-protocol population will be investigated simultaneously. Ethical considerations The protocol has been designed and developed according to the principles of the Good Clinical Practice guidelines of the International Conference on Harmonization and of the Declaration of Helsinki. The study has been approved by the Ethical Committee of the National Cancer Institute of Naples, Italy (No. 04/20). All patients will provide a written informed consent before starting treatment and blood samples collection. The privacy of patients included in the ARBITRATION study will be carefully protected by the Structure that has the responsibility for registration,.