Italian Study Of Validation Of Angiogenesis Polymorphisms In HCC Patients Treated With Sorafenib (INNOVATE)
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|ClinicalTrials.gov Identifier: NCT02786342|
Recruitment Status : Recruiting
First Posted : June 1, 2016
Last Update Posted : April 21, 2020
Sorafenib represents the standard care for advanced hepatocellular carcinoma (HCC). However, molecular predictors of sorafenib efficacy have not yet been identified.
The primary aim of the study is to validate the prognostic or predictive role of eNOS,Ang2, HIF-1, VEGF and VEGFR polymorphisms in relation to clinical outcome (progression-free survival, PFS) of HCC patients treated with sorafenib.
|Condition or disease||Intervention/treatment|
|Hepatocellular Carcinoma||Procedure: blood sample collection|
Sorafenib is a multikinase inhibitor acting on vascular endothelial growth factor receptors (VEGFR) and platelet-derived growth factor receptor beta (PDGFRβ) involved in tumor cell proliferation and tumor angiogenesis.
Angiogenesis is a cascade of linked and sequential steps ultimately leading to tumour neovascularisation. Preclinical data suggested that significant HCC growth is dependent on angiogenesis, and an increase in tumour dimension may induce vascular endothelial cell proliferation.
Vascular endothelial growth factor (VEGF)-driven pathway has been demonstrated to play a major role in tumour angiogenesis. In fact, VEGF as a potent permeability factor promotes cell migration during invasion and as an endothelial growth factor stimulates endothelial cell proliferation, inducing the budding of new blood vessels around the growing tumour masses .
Single nucleotide polymorphisms (SNPs) in VEGF and VEGF receptor (VEGFR) genes have also been correlated to tumour neoangiogenesis through different biological mechanisms.
In the ALICE-1 study HCC patients receiving sorafenib were tested for VEGF-A, VEGF-C and VEGFR-1,2,3 SNPs. At univariate analysis VEGF-A alleles C of rs25648, T of rs833061, C of rs699947, C of rs2010963, VEGF-C alleles T of rs4604006, G of rs664393, VEGFR-2 alleles C of rs2071559, C of rs2305948 were significant predictors of PFS and overall survival (OS). At multivariate analysis rs2010963, rs4604006 and Barcelona Clinic Liver Cancer (BCLC) stage resulted to be independent factors influencing PFS and OS.
In the ALICE-2 study SNPs of hypoxia inducible factor 1α (HIF-1α) were statistically significant for PFS and OS. The extended analysis of VEGF and VEGFR SNPs confirms the results of ALICE-1 study. The presence of GG genotype of rs12434438 (HIF-1α) select a population with a particularly poor outcome independently from the clinical effect of the two VEGF SNPs (PFS: 2.6 months, p<0,0001; OS: 6.6 months, p<0,0001).
In ePHAS study a training cohort of 41 HCC patients and a validation cohort of 87 patients receiving sorafenib was analyzed. At univariate analysis, patients homozygous for an endothelial nitric oxide synthase (eNOS) haplotype (HT1: T-4b at eNOS-786/eNOS VNTR) had a lower median PFS (2.6 vs. 5.8 months, p <0.0001) and OS (3.2 vs.14.6 months, p = 0.024) than those with other haplotypes. These data were confirmed in the validation set in which patients homozygous for HT1 had a lower median PFS (2.0 vs. 6.7 months, p <0.0001) and OS (6.4 vs.18.0 months, p < 0.0001).
On the basis of these premises this prospective study aims at validating the potential role of eNOS, VEGF, VEGFR, HIF-1 and Ang2 polymorphisms in patients with HCC treated with sorafenib.
|Study Type :||Observational|
|Estimated Enrollment :||160 participants|
|Official Title:||Italian Multicentric Prospective Study Of Validation Of Angiogenesis Polymorphisms In HCC Patients Treated With Sorafenib|
|Actual Study Start Date :||February 15, 2016|
|Estimated Primary Completion Date :||June 2020|
|Estimated Study Completion Date :||June 2020|
|Advanced HCC patients treated with sorafenib||
Procedure: blood sample collection
- PFS [ Time Frame: up to three years ]prognostic/predictive role of eNOS,Ang2, HIF-1, VEGF and VEGFR polymorphisms in relation to Progression Free Survival
- OS [ Time Frame: up to three years ]prognostic/predictive role of eNOS,Ang2, HIF-1, VEGF and VEGFR polymorphisms in relation to Overall Survival
Biospecimen Retention: Samples With DNA
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02786342
|Contact: Andrea Casadei-Gardini, MD||+39 0543 firstname.lastname@example.org|
|Contact: Oriana Nanni, PhD||+39 0543 email@example.com|
|IRCCS Istituto Tumori Giovanni Paolo II||Recruiting|
|Bari, BA, Italy, 70124|
|Contact: Nicola Silvestris|
|AOU di Cagliari - PO San Giovanni di Dio||Recruiting|
|Cagliari, CA, Italy, 09124|
|Contact: Mario Scartozzi|
|Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori||Recruiting|
|Meldola, FC, Italy, 47014|
|Contact: Andrea Casadei-Gardini, MD|
|Istituto Oncologico Veneto||Recruiting|
|Padova, PD, Italy, 35128|
|Contact: Vittorina Zagonel|
|Azienda Ospedaliera Universitaria Pisana||Recruiting|
|Pisa, PI, Italy, 56126|
|Contact: Gianluca Masi|
|Oncologia medica - AOU di Parma||Recruiting|
|Parma, PR, Italy, 43126|
|Contact: Francesca Negri|
|Oncologia medica , PO FAENZA, Ausl della Romagna||Recruiting|
|Faenza, RA, Italy, 48018|
|Contact: Stefano Tamberi, MD|
|Ospedale Civile degli Infermi||Recruiting|
|Rimini, RM, Italy, 47921|
|Contact: Emiliano Tamburini, MD|
|Azienda Sanitaria Universitaria Integrata di Udine S. Maria della Misericordia||Recruiting|
|Udine, UD, Italy, 33100|
|Contact: Giuseppe Aprile|
|policlinico universitario Campus Bio-medico||Recruiting|
|Roma, Italy, 00128|
|Contact: Marianna Silletta|
|Principal Investigator:||Andrea Casadei-Gardini, MD||Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST)|