Italian Study Of Validation Of Angiogenesis Polymorphisms In HCC Patients Treated With Sorafenib (INNOVATE)

February 25, 2021 updated by: Istituto Scientifico Romagnolo per lo Studio e la cura dei Tumori

Italian Multicentric Prospective Study Of Validation Of Angiogenesis Polymorphisms In HCC Patients Treated With Sorafenib

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.

Study Overview

Status

Active, not recruiting

Conditions

Intervention / Treatment

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.

Study Type

Observational

Enrollment (Anticipated)

160

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Italy
      • Roma, Italy, 00128
        • Policlinico Universitario Campus Bio-Medico
    • BA
      • Bari, BA, Italy, 70124
        • Irccs Istituto Tumori Giovanni Paolo Ii
    • CA
      • Cagliari, CA, Italy, 09124
        • AOU di Cagliari - PO San Giovanni di Dio
    • FC
      • Meldola, FC, Italy, 47014
        • Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori
    • PD
      • Padova, PD, Italy, 35128
        • Istituto Oncologico Veneto
    • PI
      • Pisa, PI, Italy, 56126
        • Azienda Ospedaliera Universitaria Pisana
    • PR
      • Parma, PR, Italy, 43126
        • Oncologia medica - AOU di Parma
    • RA
      • Faenza, RA, Italy, 48018
        • Oncologia medica , PO FAENZA, Ausl della Romagna
    • RM
      • Rimini, RM, Italy, 47921
        • Ospedale Civile degli Infermi
    • UD
      • Udine, UD, Italy, 33100
        • Azienda Sanitaria Universitaria Integrata di Udine S. Maria della Misericordia

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

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)

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Observational Models: Cohort
  • Time Perspectives: Prospective

Cohorts and Interventions

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

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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
up to three years

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
OS
Time Frame: up to three years
prognostic/predictive role of eNOS,Ang2, HIF-1, VEGF and VEGFR polymorphisms in relation to Overall Survival
up to three years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Istituto Scientifico Romagnolo per lo Studio e la cura dei Tumori

Investigators

  • Principal Investigator: Andrea Casadei-Gardini, MD, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST)

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

February 15, 2016

Primary Completion (Anticipated)

June 1, 2021

Study Completion (Anticipated)

June 1, 2021

Study Registration Dates

First Submitted

May 20, 2016

First Submitted That Met QC Criteria

May 25, 2016

First Posted (Estimate)

June 1, 2016

Study Record Updates

Last Update Posted (Actual)

February 26, 2021

Last Update Submitted That Met QC Criteria

February 25, 2021

Last Verified

February 1, 2021

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • IRSTB051

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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