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Start Over Author "Francesca Bruzzese" Journal bmc cancer
2 results on '"Francesca Bruzzese"'

1. Randomized phase 2 study of valproic acid combined with simvastatin and gemcitabine/nab-paclitaxel-based regimens in untreated metastatic pancreatic adenocarcinoma patients: the VESPA trial study protocol

Author

Alfredo Budillon, Alessandra Leone, Eugenia Passaro, Lucrezia Silvestro, Francesca Foschini, Federica Iannelli, Maria Serena Roca, Marina Macchini, Francesca Bruzzese, Maria Laura Garcia Bermejo, Mercedes Rodriguez Garrote, Giampaolo Tortora, Michele Milella, Michele Reni, Claudia Fuchs, Eve Hewitt, Christine Kubiak, Elena Di Gennaro, Diana Giannarelli, and Antonio Avallone

Subjects
Pancreatic cancer, Valproic acid, Simvastatin, Drug repurposing, Gemcitabine, nab-paclitaxel, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract Background Metastatic pancreatic ductal adenocarcinoma (mPDAC) patients have very poor prognosis highlighting the urgent need of novel treatments. In this regard, repurposing non-oncology already-approved drugs might be an attractive strategy to offer more-effective treatment easily tested in clinical trials. Accumulating evidence suggests that epigenetic deregulation is a hallmark of cancer contributing to treatment resistance in several solid tumors, including PDAC. Histone deacetylase inhibitors (HDACi) are epigenetic drugs we have investigated preclinically and clinically as anticancer agents. Valproic acid (VPA) is a generic low-cost anticonvulsant and mood stabilizer with HDAC inhibitory activity, and anticancer properties also demonstrated in PDAC models. Statins use was reported to be associated with lower mortality risk in patients with pancreatic cancer and statins have been shown to have a direct antitumor effect when used alone or in combination therapy. We recently showed capability of VPA/Simvastatin (SIM) combination to potentiate the antitumor activity of gemcitabine/nab-paclitaxel in vitro and in vivo PDAC preclinical models. Methods/Design VESPA is a patient-centric open label randomized multicenter phase-II investigator-initiated trial, evaluating the feasibility, safety, and efficacy of VPA/SIM plus first line gemcitabine/nab-paclitaxel-based regimens (AG or PAXG) (experimental arm) versus chemotherapy alone (standard arm) in mPDAC patients. The study involves Italian and Spanish oncology centers and includes an initial 6-patients safety run-in-phase. A sample size of 240 patients (120 for each arm) was calculated under the hypothesis that the addition of VPA/SIM to gemcitabine and nab-paclitaxel-based regimens may extend progression free survival from 6 to 9 months in the experimental arm. Secondary endpoints are overall survival, response rate, disease control rate, duration of response, CA 19.9 reduction, toxicity, and quality of life. The study includes a patient engagement plan and complementary biomarkers studies on tumor and blood samples. Conclusions VESPA is the first trial evaluating efficacy and safety of two repurposed drugs in oncology such as VPA and SIM, in combination with standard chemotherapy, with the aim of improving mPDAC survival. The study is ongoing. Enrollment started in June 2023 and a total of 63 patients have been enrolled as of June 2024. Trial registration EudraCT number: 2022-004154-63; ClinicalTrials.gov identifier NCT05821556, posted 2023/04/20.

Published
2024
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2. Phase II clinical study of valproic acid plus cisplatin and cetuximab in recurrent and/or metastatic squamous cell carcinoma of Head and Neck-V-CHANCE trial

Author

Gerardo Botti, Antonella Petrillo, Francesco Caponigro, Francesca Bruzzese, M.G. Maglione, Fabio Sandomenico, Alfredo Budillon, Nunzia Simona Losito, Rossella De Cecio, Massimiliano Di Marzo, Paolo Muto, Ernesta Cavalcanti, Gianfranco De Feo, Stefania Scala, Roberta D’Aniello, Francesco Longo, Elena Di Gennaro, Andrea Ilaria Zotti, Corrado Aversa, Monica Pontone, Antonio Daponte, Piera Maiolino, Ettore Pavone, Franco Ionna, Massimo Montano, Ester Calogero, Francesco Perri, and Annamaria Trotta

Subjects
0301 basic medicine, Oncology, Male, medicine.medical_specialty, Cancer Research, medicine.drug_class, Cetuximab, Administration, Oral, Drug Administration Schedule, 03 medical and health sciences, Study Protocol, 0302 clinical medicine, Internal medicine, Antineoplastic Combined Chemotherapy Protocols, medicine, Genetics, Humans, Neoplasm Metastasis, Vorinostat, Cisplatin, Histone deacetylase inhibitor, business.industry, Squamous Cell Carcinoma of Head and Neck, Valproic Acid, Head and neck cancer, Head and Neck cancer, medicine.disease, Chemotherapy regimen, Survival Analysis, 030104 developmental biology, Treatment Outcome, Response Evaluation Criteria in Solid Tumors, Head and Neck Neoplasms, 030220 oncology & carcinogenesis, Carcinoma, Squamous Cell, Female, Histone deacetylase, Neoplasm Recurrence, Local, business, medicine.drug
Abstract

Background Recurrent/metastatic squamous cell carcinoma of the head and neck (SCCHN) has a poor prognosis and the combination of cisplatin and cetuximab, with or without 5-fluorouracil, is the gold standard treatment in this stage. Thus, the concomitant use of novel compounds represents a critical strategy to improve treatment results. Histone deacetylase inhibitors (HDACi) enhance the activity of several anticancer drugs including cisplatin and anti-Epidermal Growth Factor Receptor (anti-EGFR) compounds. Preclinical studies in models have shown that vorinostat is able to down regulate Epidermal Growth Factor Receptor (EGFR) expression and to revert epithelial to mesenchimal transition (EMT). Due to its histone deacetylase (HDAC) inhibiting activity and its safe use as a chronic therapy for epileptic disorders, valproic acid (VPA) has been considered a good candidate for anticancer therapy. A reasonable option may be to employ the combination of cisplatin, cetuximab and VPA in recurrent/metastatic SCCHN taking advantage of the possible positive interaction between histone deacetylase inhibitors, cisplatin and/or anti-EGFR. Method/Design V-CHANCE is a phase 2 clinical trial evaluating, in patients with recurrent/metastatic squamous cell carcinoma of the head and neck never treated with first-line chemotherapy, the concomitant standard administration of cisplatin (on day 1, every 3 weeks) and cetuximab (on day 1, weekly), in combination with oral VPA given daily from day −14 with a titration strategy in each patient (target serum level of 50–100 μg/ml). Primary end point is the objective response rate measured according to Response Evaluation Criteria in Solid Tumors (RECIST). Sample size, calculated according to Simon 2 stage minimax design will include 21 patients in the first stage with upper limit for rejection being 8 responses, and 39 patients in the second stage, with upper limit for rejection being 18 responses. Secondary endpoints are time to progression, duration of response, overall survival, safety. Objectives of the translational study are the evaluation on tumor samples of markers of treatment efficacy/resistance (i.e. γH2AX, p21/WAF, RAD51, XRCC1, EGFR, p-EGFR, Ki-67) and specific markers of VPA HDAC inhibitory activity (histones and proteins acetylation, Histone deacetylase isoforms) as well as valproate test, histones and proteins acetylation of peripheral blood mononuclear cell, tested on blood samples at baseline and at different time points during treatment. Discussion Overall, this study could provide a less toxic and more effective first-line chemotherapy regimen in patients with recurrent/metastatic squamous cell carcinoma of the head and neck by demonstrating the feasibility and efficacy of cisplatin/cetuximab plus valproic acid. Moreover, correlative studies could help to identify responder patients, and will add insights in the mechanism of the synergistic interaction between these agents. EudraCT Number 2014-001523-69 Trial registration ClinicalTrials.gov number, NCT02624128

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