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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
Sponsor:
Information provided by (Responsible Party):
Istituto Scientifico Romagnolo per lo Studio e la cura dei Tumori

Brief Summary:

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

Detailed Description:

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.

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Study Type : Observational
Estimated Enrollment : 160 participants
Observational Model: Cohort
Time Perspective: Prospective
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

Resource links provided by the National Library of Medicine

Drug Information available for: Sorafenib

Group/Cohort Intervention/treatment
Advanced HCC patients treated with sorafenib Procedure: blood sample collection



Primary Outcome Measures :
  1. 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


Secondary Outcome Measures :
  1. 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
Whole Blood, plasma and serum samples.


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Probability Sample
Study Population
The study population consists of patients with advanced-stage hepatocellular carcinoma, according to the criteria American Association for the Study of Liver Disease (AASLD) / European Association for the Study of the Liver (EASL)
Criteria

Inclusion Criteria:

  1. Signed and dated informed consent.
  2. Ability to understand and the willingness to sign a written informed consent document.
  3. Male or Female, aged >18 years.
  4. Eastern Cooperative Oncology Group (ECOG) performance status score of 2 or less.
  5. Life expectancy of 12 weeks or more.
  6. Adequate hematologic function.
  7. Patients were required to have at least one untreated target lesion that could be measured in one dimension, according to the Response Evaluation Criteria in Solid Tumors (RECIST version 1.1).
  8. Concomitant antiviral systemic therapy was allowed.
  9. Resolution of all acute toxic effects of any prior local treatment.
  10. HCC diagnosed according to the AASLD and/or EASL criteria.

Exclusion Criteria:

  1. Previous or concurrent cancer that is distinct in primary site or histology from HCC.
  2. Renal failure requiring hemo- or peritoneal dialysis.
  3. Presence of recent (< 6 months) or current cardiac failure Known history of human immunodeficiency virus (HIV) infection.
  4. Known central nervous system tumors including metastatic brain disease.
  5. Patients with clinically significant gastrointestinal bleeding within 30 days prior to study entry.
  6. Any prior local therapy within 4 weeks of study entry.
  7. Pregnancy or breastfeeding.

Information from the National Library of Medicine

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


Contacts
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Contact: Andrea Casadei-Gardini, MD +39 0543 739100 andrea.casadei@irst.emr.it
Contact: Oriana Nanni, PhD +39 0543 739100 o.nanni@irst.emr.it

Locations
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Italy
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         
Sponsors and Collaborators
Istituto Scientifico Romagnolo per lo Studio e la cura dei Tumori
Investigators
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Principal Investigator: Andrea Casadei-Gardini, MD Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST)
Publications:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Istituto Scientifico Romagnolo per lo Studio e la cura dei Tumori
ClinicalTrials.gov Identifier: NCT02786342    
Other Study ID Numbers: IRSTB051
First Posted: June 1, 2016    Key Record Dates
Last Update Posted: April 21, 2020
Last Verified: April 2020
Keywords provided by Istituto Scientifico Romagnolo per lo Studio e la cura dei Tumori:
Hepatocellular Carcinoma
Sorafenib
HCC
Angiogenesis
Polymorphisms
Additional relevant MeSH terms:
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Carcinoma, Hepatocellular
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Adenocarcinoma
Liver Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Digestive System Diseases
Liver Diseases