REINVENT (REgorafenIb traNslational eValuation angiogENesis proTocol)

Abstract

Background: The introduction of regorafenib represented a significant step forward for metastatic colorectal cancer patients. Available data seem to indicate that a not negligible proportion of patients does not derive any benefit from this treatment and is thus exposed to unnecessary toxicity. Preliminary findings from our group suggested that vascular endothelial growth factor-A (VEGF-A) rs2010963 might have an independent correlation with progression free (PFS) and overall survival (OS). On the other hand further analyses focused on factors such as neutrophil to lymphocyte ratio, platelets count and LDH serum levels to define a biological profile of responding/ resistant patients. Unfortunately these factors have been all analyzed separately and, more importantly, retrospectively. Avalidation is mandatory prior to incorporate findings from these studies into clinical practice. Trial design: The REINVENT is a multicenter, biologically enriched study. Primary objective is to define a clinical and molecular panel able to identify patients more likely to benefit from the use of regorafenib in terms of PFS. Secondary objectives are OS and Response Rate and the evaluation of VEGF PlGF, HGF, VEGF-R, ANG-2, IL-6, IL-8 plasma concentrations as prognostic factors and potential markers of early progression. Metastatic colorectal cancer patients, progressing after all indicated treatments, receiving regorafenib as per label are prospectively divided into 2 prognostic groups: favorable and unfavorable. Patients harboring VEGFA rs2010963, without high platelet count or low lymphocyte count or high NLR are allocated to favorable group; patients not harboring VEGFA s2010963 and/or having high platelet count and/or low lymphocyte count and/or high NLR are allocated to unfavorable group. Group allocation is blinded to treating physician. Investigators will assess tumor response and progression every 8 weeks according to the Response Evaluation Criteria in Solid Tumors (RECIST v 1.1). To detect a difference in terms of PFS at 6 months among patients with an unfavorable profile and patients with an optimal profile, assuming a probability alpha of 0.05 and beta of 0.05, required sample size will be 250 patients.