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

Hepatocellular Carcinoma Clinical Trial

— INNOVATE  

Official title:

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT02786342
• Other study ID #: IRSTB051
• Status: Active, not recruiting
• Start date: February 15, 2016
• Est. completion date: June 2021

Study information

• Verified date: February 2021
• Source: Istituto Scientifico Romagnolo per lo Studio e la cura dei Tumori
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 160
• Est. completion date: June 2021
• Est. primary completion date: June 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Carcinoma, Hepatocellular
• Hepatocellular Carcinoma

Intervention

Procedure:
• blood sample collection

Locations

Country	Name	City	State
Italy	IRCCS Istituto Tumori Giovanni Paolo II	Bari	BA
Italy	AOU di Cagliari - PO San Giovanni di Dio	Cagliari	CA
Italy	Oncologia medica , PO FAENZA, Ausl della Romagna	Faenza	RA
Italy	Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori	Meldola	FC
Italy	Istituto Oncologico Veneto	Padova	PD
Italy	Oncologia medica - AOU di Parma	Parma	PR
Italy	Azienda Ospedaliera Universitaria Pisana	Pisa	PI
Italy	Ospedale Civile degli Infermi	Rimini	RM
Italy	policlinico universitario Campus Bio-medico	Roma
Italy	Azienda Sanitaria Universitaria Integrata di Udine S. Maria della Misericordia	Udine	UD

Sponsors (1)

Lead Sponsor	Collaborator
Istituto Scientifico Romagnolo per lo Studio e la cura dei Tumori

Country where clinical trial is conducted

Italy, 

References & Publications (2)

Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, de Oliveira AC, Santoro A, Raoul JL, Forner A, Schwartz M, Porta C, Zeuzem S, Bolondi L, Greten TF, Galle PR, Seitz JF, Borbath I, Häussinger D, Giannaris T, Shan M, Moscovici M, Voliotis D, Bruix J; SHARP Investigators Study Group. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008 Jul 24;359(4):378-90. doi: 10.1056/NEJMoa0708857. — View Citation

Scartozzi M, Faloppi L, Svegliati Baroni G, Loretelli C, Piscaglia F, Iavarone M, Toniutto P, Fava G, De Minicis S, Mandolesi A, Bianconi M, Giampieri R, Granito A, Facchetti F, Bitetto D, Marinelli S, Venerandi L, Vavassori S, Gemini S, D'Errico A, Colombo M, Bolondi L, Bearzi I, Benedetti A, Cascinu S. VEGF and VEGFR genotyping in the prediction of clinical outcome for HCC patients receiving sorafenib: the ALICE-1 study. Int J Cancer. 2014 Sep 1;135(5):1247-56. doi: 10.1002/ijc.28772. Epub 2014 Feb 20. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	PFS	prognostic/predictive role of eNOS,Ang2, HIF-1, VEGF and VEGFR polymorphisms in relation to Progression Free Survival	up to three years
Secondary	OS	prognostic/predictive role of eNOS,Ang2, HIF-1, VEGF and VEGFR polymorphisms in relation to Overall Survival	up to three years