Clinical trial NCT02786342: Italian Study Of Validation Of Angiogenesis Polymorphisms In HCC Patients Treated With Sorafenib
Official title: Italian Multicentric Prospective Study Of Validation Of Angiogenesis Polymorphisms In HCC Patients Treated With Sorafenib
Study type: OBSERVATIONAL
Overall status: UNKNOWN
Conditions: Hepatocellular Carcinoma
Keywords: Hepatocellular Carcinoma
Sorafenib
HCC
Angiogenesis
Polymorphisms
Lead sponsor: Istituto Romagnolo per lo Studio dei Tumori Dino Amadori IRST S.r.l. IRCCS
Sponsor class: OTHER
First posted: 2016-06-01
Enrollment: 160
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
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)

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.

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.

Eligibility 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.

Primary outcomes:
measure: PFS
timeFrame: up to three years
Secondary outcomes:
measure: OS
timeFrame: up to three years
Other outcomes:
Locations:
city: Bari
country: Italy
facility: IRCCS Istituto Tumori Giovanni Paolo II
state: BA
city: Cagliari
country: Italy
facility: AOU di Cagliari - PO San Giovanni di Dio
state: CA
city: Meldola
country: Italy
facility: Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori
state: FC
city: Padova
country: Italy
facility: Istituto Oncologico Veneto
state: PD
city: Pisa
country: Italy
facility: Azienda Ospedaliera Universitaria Pisana
state: PI
city: Parma
country: Italy
facility: Oncologia medica - AOU di Parma
state: PR
city: Faenza
country: Italy
facility: Oncologia medica , PO FAENZA, Ausl della Romagna
state: RA
city: Rimini
country: Italy
facility: Ospedale Civile degli Infermi
state: RM
city: Udine
country: Italy
facility: Azienda Sanitaria Universitaria Integrata di Udine S. Maria della Misericordia
state: UD
city: Roma
country: Italy
facility: policlinico universitario Campus Bio-medico
Study officials:
affiliation: Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST)
name: Andrea Casadei-Gardini, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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, Haussinger 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.
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.
citation: Casadei-Gardini A, Marisi G, Dadduzio V, Gramantieri L, Faloppi L, Ulivi P, Foschi FG, Tamburini E, Vivaldi C, Rizzato MD, Ielasi L, Canale M, Conti F, Rudnas B, Fornaro L, Silvestris N, Silletta M, Cardellino GG, Lonardi S, Fornari F, Orsi G, Rovesti G, Zagonel V, Cascinu S, Scartozzi M. Association of NOS3 and ANGPT2 Gene Polymorphisms with Survival in Patients with Hepatocellular Carcinoma Receiving Sorafenib: Results of the Multicenter Prospective INNOVATE Study. Clin Cancer Res. 2020 Sep 1;26(17):4485-4493. doi: 10.1158/1078-0432.CCR-19-3897. Epub 2020 May 5.