Prospective Study of VEGFR-2 /IL-8 Genetic Interaction in MBC Treated With Paclitaxel and Bevacizumab vs. Chemotherapy

Metastatic Breast Cancer Clinical Trial

— BEVAPROS  

Official title:

Prospective Evaluation of VEGFR-2 rs11133360/IL-8 rs4073 Genetic Interaction in Metastatic Breast Cancer Patients Treated With Paclitaxel and Bevacizumab vs. Chemotherapy Alone (BEVAPROS)

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT02329639
• Other study ID #: University of Pisa - Az. USL 5
• Status: Recruiting
• Phase: N/A
• First received: December 29, 2014
• Last updated: October 24, 2017
• Start date: April 2014
• Est. completion date: July 2018

Study information

• Verified date: October 2017
• Source: University of Pisa
• Contact: Giacomo Allegrini, MD
• Phone: +39-0587-273104
• Email: g.allegrini[@]usl5.toscana.it
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

Metastatic Breast cancer (MBC) patients from ten Italian Divisions of Medical Oncology, with histologically confirmed HER2-negative MBC, treated with a first-line therapy including bevacizumab 10 mg/m2 i.v. on days 1 and 15 combined with first-line paclitaxel 90 mg/m2 i.v. on days 1,8 and 15, every 4 weeks, will be enrolled for the present pharmacogenetic study. MBC patients treated with first-line chemotherapy including paclitaxel without bevacizumab will be also enrolled as control group.

Description:

Metastatic Breast Cancer (MBC) patients from ten Italian Divisions of Medical Oncology, with histologically confirmed HER2-negative MBC, treated with a first-line therapy including bevacizumab 10 mg/m2 i.v. on days 1 and 15 combined with first-line paclitaxel 90 mg/m2 i.v. on days 1,8 and 15, every 4 weeks, will be enrolled for the present pharmacogenetic study. MBC patients treated with a first-line chemotherapy without bevacizumab will be also enrolled as control group. Sites of metastatic disease will be radiologically re-evaluated according to the Response Evaluation Criteria in Solid Tumors (RECIST) criteria 1.1, in patients with measurable disease. In patients without measurables lesions, progression of disease will be defined when new lesions appeared or when existing lesions evolved. In the case of non measurables lesions, deterioration of clinical condition not due to treatment toxicity, will be defined as progression disease. Progression-free survival (PFS), will be defined as the period of time from the beginning of the treatment to the first observation of disease progression as above described, or death from any cause. All patients will be for response, PFS and overall survival. Each patient entering the study will sign the informed consent. The protocol has been approved by Ethics Committee Vast Area Northwest of Tuscany (CEAVNO), Pisa, Italy (30/04/2014). Genotyping analyses blood samples (3 ml.) will be collected in ethylenediaminetetraacetic acid tubes and stored at -80° C. Genes and polymorphisms involved in the angiogenesis pathway and already suggested as predictors of bevacizumab response, will be chosen for the present analyses. Germline DNA extraction will be performed using QIamp DNA Blood Mini Kit (Qiagen, Valencia, California, USA). Allelic discrimination of genes will be performed using an ABI PRISM 7900 SDS Instrument (Applied Biosystems, Carlsbad, California, USA) and with validated TaqMan single nucleotide polymorphism (SNP) genotyping assays (Applied Byosistems). Polymerase chain reactions will be carried out according to the manufacturer's protocol. Genotyping will be not performed until an adequate number of events (>80% on study population) will be reported in terms of PFS. Statistical analysis: The first aim of this prospective analysis will be evaluate the possible role of VEGFR-2 rs11133360/IL-8 rs4073 polymorphism genetic interaction to predict the bevacizumab response in terms of PFS. The secondary end-points will be the correlations with overall survival (OS) and response rate. All polymorphisms will be analyzed for deviation from the Hardy-Weinberg Equilibrium (HWE) by means of comparison between observed allelic distributions with those expected from the HWE by on x2 test. Any correlation between gene polymorphisms and response rate will be analyzed by the two-sided Fisher's Exact Test. The association between each individual polymorphism and the most relevant clinical-pathological characteristics with PFS will be tested using a Cox proportional hazards model. The Multifactor Dimensionality Reduction (MDR) methodology will be applied (using version 2.0 beta 6 of MDR software available on http://sourceforge.net/projects/mdr/) to investigate the role of an interaction between gene polymorphisms in identifying biomarkers of paclitaxel plus bevacizumab response. The genotype combination with the highest PFS benefit correlated with an OS improvement will be chosen for further analyses. The difference in PFS between favourable genetic profiles and the unfavourable genetic profiles will be assessed with the log-rank test and the kaplan-Meier method to evaluate survival curves. A Cox proportional hazards model, with the possible genetic profiles and the clinical and pathological patient characteristics individually correlated with the PFS, will be used to calculate the adjusted hazards ratio (HR) and the 95% confidence interval (95% CI). A P value of<0.05 will be accepted as statistically significant. Tha Kaplan-Meier and Cox proportional hazards analyses will be performed using the SPSS version 17.0 (SPSS, Chicago, IL).

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 189
• Est. completion date: July 2018
• Est. primary completion date: March 2018
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• histologically confirmed HER2-negative MBC, treated with a first-line therapy including bevacizumab 10 mg/m2 i.v. on days 1 and 15 combined with first-line paclitaxel 90 mg/m2 i.v. on days 1,8 and 15,every 4 weeks, will be enrolled for the present pharmacogenetic study. MBC patients treated with a first-line chemotherapy without bevacizumab will also be enrolled as control goup.

Exclusion Criteria:

• histologically not confirmed HER2-negative MBC, and patients not treated with a first-line chemotherapy with or without bevacizumab.

Related Conditions & MeSH terms

• Breast Neoplasms
• Metastatic Breast Cancer

Intervention

Genetic:
• genetic interaction analysis
VEGFR-2 rs11133360/IL-8 rs4073 genetic interaction analysis

Locations

Country	Name	City	State
Italy	Department of Clinical and Experimental Medicine, University of Pisa	Pisa	I am not in the U.S. or Canada
Italy	Azienda USL 5 of Pisa	Pontedera	Pisa

Sponsors (1)

Lead Sponsor	Collaborator
University of Pisa

Country where clinical trial is conducted

Italy, 

References & Publications (1)

Allegrini G, Coltelli L, Orlandi P, Fontana A, Camerini A, Ferro A, Cazzaniga M, Casadei V, Lucchesi S, Bona E, Di Lieto M, Pazzagli I, Villa F, Amoroso D, Scalese M, Arrighi G, Molinaro S, Fioravanti A, Finale C, Triolo R, Di Desidero T, Donati S, Marcucci L, Goletti O, Del Re M, Salvadori B, Ferrarini I, Danesi R, Falcone A, Bocci G. Pharmacogenetic interaction analysis of VEGFR-2 and IL-8 polymorphisms in advanced breast cancer patients treated with paclitaxel and bevacizumab. Pharmacogenomics. 2014 Dec;15(16):1985-99. doi: 10.2217/pgs.14.140. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Progression free survival	progression free survival in an unselected population of metastatic breast cancer patients treated with first-line paclitaxel and bevacizumab or with chemotherapy alone, assessed through the multifactor dimensionality reduction methodology (genetic interaction analysis)	24 months
Secondary	Overall survival	overall survival in an unselected population of metastatic breast cancer patients treated with first-line paclitaxel and bevacizumab or with chemotherapy alone, assessed through the multifactor dimensionality reduction methodology (genetic interaction analysis)	24 months