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.

Humans Valproic Acid / therapeutic use Pancreatic Neoplasms / drug therapy Simvastatin / administration & dosage Antineoplastic Combined Chemotherapy Protocols / therapeutic use Gemcitabine Deoxycytidine / analogs & derivatives Paclitaxel / administration & dosage Albumins / administration & dosage Female Male Carcinoma, Pancreatic Ductal / drug therapy Middle Aged Aged Drug Repositioning / methods Adult

Drug repurposing Gemcitabine, nab-paclitaxel Pancreatic cancer Simvastatin Valproic acid

Journal

BMC cancer

ISSN: 1471-2407

Titre abrégé: BMC Cancer

Pays: England

ID NLM: 100967800

Informations de publication

Date de publication:
19 Sep 2024

Historique:

received: 03 09 2024

accepted: 11 09 2024

medline: 20 9 2024

pubmed: 20 9 2024

entrez: 19 9 2024

Statut: epublish

Résumé

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. 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. 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. EudraCT number: 2022-004154-63; ClinicalTrials.gov identifier NCT05821556, posted 2023/04/20.

Sections du résumé

BACKGROUND BACKGROUND

METHODS/DESIGN METHODS

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 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 BACKGROUND

EudraCT number: 2022-004154-63; ClinicalTrials.gov identifier NCT05821556, posted 2023/04/20.

Identifiants

DOI: 10.1186/s12885-024-12936-w PMID: 39300376

pubmed: 39300376

doi: 10.1186/s12885-024-12936-w

pii: 10.1186/s12885-024-12936-w

doi:

Substances chimiques

Valproic Acid 614OI1Z5WI

Simvastatin AGG2FN16EV

Gemcitabine 0

Deoxycytidine 0W860991D6

Paclitaxel P88XT4IS4D

130-nm albumin-bound paclitaxel 0

Albumins 0

Banques de données

ClinicalTrials.gov

['NCT05821556']

Types de publication

Journal Article Clinical Trial Protocol Multicenter Study Clinical Trial, Phase II Randomized Controlled Trial

Langues

eng

Sous-ensembles de citation

Pagination

1167

Subventions

Organisme : European Union's Horizon Europe research and innovation

ID : 101057442

Organisme : Ministero della Salute

ID : RF-2021-12371995

Informations de copyright

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