Phase 2 Randomized Study of Valproic Acid, Simvastatin, and Gemcitabine/Nab-Paclitaxel Regimens in Metastatic Pancreatic Ductal Adenocarcinoma
- Trial ID
- 2024-518710-11-00
- Protocol
- VESPA
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this randomized phase 2 study is to evaluate whether the combination of **valproic acid** and **simvastatin** with gemcitabine/nab-paclitaxel-based regimens can enhance the efficacy of first-line treatment in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC). This is clinically relevant as improving the efficacy of existing treatment regimens could potentially lead to better patient outcomes in this aggressive cancer type.
Secondary objectives include:
- Exploring the feasibility, efficacy, and safety of this novel combined approach in first-line mPDAC patients and assessing its impact on their quality of life.
- Conducting correlative studies on tumor and blood samples to identify potential biomarkers of toxicity and efficacy, which may provide new insights into the antitumor mechanism of the VPA/SIM combination with chemotherapy.
Participants
The clinical trial involves participants diagnosed with **metastatic pancreatic ductal adenocarcinoma (mPDAC)**. The study population includes both male and female subjects aged 18 years and older. Participants are required to have a histologically or cytologically confirmed diagnosis of metastatic PDAC and must not have received any prior treatments for mPDAC. The trial population was selected based on specific inclusion criteria, including an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1, and adequate bone marrow, liver, and renal function. The trial does not specify the total number of participants, as the sponsor has not provided this information. The study considers a vulnerable population, and participants must provide written informed consent. Lifestyle factors such as diet and physical activity are not explicitly mentioned as considerations for this trial.
Plans and Procedures
The clinical trial is designed as a **randomized**, **double-blind**, and controlled study to evaluate the efficacy of a combination therapy in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC). The trial aims to assess whether the combination of **valproic acid** and **simvastatin** with **gemcitabine**/**nab-paclitaxel**-based regimens can improve the efficacy of first-line treatments. The study is expected to run until December 31, 2026, with recruitment having started on June 14, 2023.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as histologically or cytologically proven mPDAC, no prior treatments for mPDAC, and adequate organ function. Following randomization, participants will receive treatment over a maximum period of six months, with regular follow-up visits to monitor progression-free survival (PFS), objective tumor response rate (ORR), and other secondary endpoints such as overall survival (OS) and quality of life (QoL).
The end-of-study visit will occur at the conclusion of the treatment period or upon early termination. Conditions that may lead to early termination include disease progression, unacceptable toxicity, or withdrawal of consent. Participant involvement is expected to last for the duration of the treatment period, with additional follow-up as necessary to assess long-term outcomes. The trial will utilize **RECIST 1.1 criteria** to evaluate disease progression and response to treatment, ensuring a standardized approach to data collection and analysis.
Treatment
The clinical trial involves the administration of several **experimental medications** and **non-experimental treatments** to evaluate their efficacy in patients with metastatic pancreatic ductal adenocarcinoma. The **experimental medication** **CISPLATIN** is administered as an infusion. It is a platinum-based chemotherapy agent used to treat various tumors. The dosage is measured in milligrams per square meter (mg/m²), with a maximum daily dose of 30 mg/m² and a total maximum dose of 360 mg/m² over a treatment period of up to 6 cycles.
**Abraxane**, containing **PACLITAXEL ALBUMIN-BOUND**, is provided as a powder for dispersion for infusion. The maximum daily dose is 125 mg/m², with a total maximum dose of 2700 mg/m² over 6 cycles. This medication is part of the nab-paclitaxel-based regimens being evaluated in the trial.
**SIMVASTATIN** is administered orally in the form of film-coated tablets. It is classified as an HMG-CoA reductase inhibitor (statin). The maximum daily dose is 20 mg, with a total maximum dose of 3600 mg over a 6-cycle treatment period.
**VALPROIC ACID** is provided in two formulations: modified-release tablets and prolonged-release tablets, both administered orally. The modified-release formulation has a maximum daily dose of 300 mg, with a total maximum dose of 300 mg over 5 cycles. The prolonged-release formulation has a maximum daily dose of 1500 mg, with a total maximum dose of 270,000 mg over 6 cycles. Valproic acid is an anticonvulsant drug used in the treatment of various conditions.
**CAPECITABINE** is administered orally in tablet form. The maximum daily dose is 1250 mg/m², with a total maximum dose of 22,500 mg/m² over 6 cycles. This medication is part of the chemotherapy regimen being evaluated in the trial.
**GEMCITABINE** is administered as a solution for infusion. It belongs to the nucleoside analog family of medications and is classified as an antimetabolite. The maximum daily dose is 1000 mg/m², with a total maximum dose of 12,000 mg/m² over 6 cycles.
Participant compliance with the dosing schedules is monitored throughout the trial to ensure adherence to the treatment protocols. The trial aims to assess the potential improvement in efficacy when combining valproic acid and simvastatin with gemcitabine/nab-paclitaxel-based regimens in the treatment of metastatic pancreatic ductal adenocarcinoma.
Efficacy
Efficacy in the clinical trial will be assessed using both primary and secondary endpoints. The primary endpoint is **Progression Free Survival (PFS)**, which is defined as the time from randomization to the first documentation of objective disease progression according to RECIST 1.1 criteria, or death due to any cause, whichever occurs first. PFS will be censored at the time of the last available tumor assessment documenting the absence of progressive disease for patients alive at the time of analysis.
Secondary endpoints include the comparison of the two treatment arms in terms of Objective Tumor Response Rate (ORR), Disease Control Rate (DCR), Duration of Objective Response (DOR), CA19.9 level reduction, Overall Survival (OS), Overall Toxicity Rate, and Quality of Life (QoL). Additionally, mechanistically-based pharmacokinetic and pharmacodynamic biomarkers will be evaluated on blood samples. Prognostic factors and predictive biomarkers for response and toxicity will also be explored on blood samples, as well as primary tumors and resected metastases when available.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Written informed consent to study procedures and to correlative studies.
- Histologically or cytologically proven metastatic PDAC
- No prior treatments (chemotherapy, radiation or surgery) for mPDAC
- Eastern Cooperative Oncology Group (ECOG) Performance Status ≤1 at study entry.
- Imaging-documented measurable disease, according to RECIST 1.1 criteria.
- Either sex aged ≥ 18
- Known dihydropyrimidine dehydrogenase (DPD) activity is mandatory for patients enrolled in PAXG scheme
- Adequate bone marrow haematological function: absolute neutrophil count (!NC) ≥ 1/5 x 109/L AND platelet count ≥ 100 x 109/L !ND haemoglobin ≥ 9 g/dL
- Adequate liver function. total bilirubin ≤ 1/5 x upper limit of normal (ULN) or ≤ 2 (in case of biliary stent) and aspartate aminotransferase (AST)/alanine aminotransferase (!LT) ≤ 5 X ULN/ Adequate renal function. serum creatinine ≤ 1/5 mg/dL OR creatinine clearance ≥ 60 mL/min in males and ≥50 mL/min in females (calculated according to Cockroft-Gault formula).
Exclusion Criteria
- Prior malignancy within one year. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer.
- Prior chemotherapy or any other medical treatment for metastatic PDAC (previous adjuvant chemotherapy is allowed if terminated > 6 months previously).
- Patients who have had prior treatment with an HDAC inhibitor and patients who have received compounds with HDAC inhibitor-like activity, such as valproic acid.
- Current use of statins or fibrates or any medication for hypercholesterolemia for any time during the 3 months before the study.
- Proven hypersensitivity to statins and to any component of the other medications used in the trial.
- Major surgical intervention within 4 weeks prior to enrollment.
- Pregnancy and breast-feeding.
- Brain metastasis
- Hepatitis or any severe liver disorder
- Evidence of severe or uncontrolled systemic disease or any concurrent condition which in the investigator’s opinion makes it undesirable for the patient to participate in the study, or which would jeopardize compliance with the protocol, or would interfere with the results of the study.
- Patients with long QT-syndrome or QTc interval duration > 480 msec or concomitant medication with drugs prolonging QTc
- History of poor co-operation, non-compliance with medical treatment, unreliability or any condition that may impair the patient’s understanding of the Informed consent form
- Participation in any interventional drug study within 30 days prior to treatment start.
- Patients who cannot take oral medication, who require intravenous alimentation, have had prior surgical procedures affecting absorption, or have active peptic ulcer disease
- Sexually active males and females (of childbearing potential) unwilling to practice contraception during the study and until 6 months after the last trial treatment.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Italy | Recruiting | 14 Jun 2023 | 150 |
 Spain | Recruiting | 14 Jun 2023 | 20 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
VALPROIC ACID | Test | — | ORAL | 300 | 5 | SUB00015MIG |
CISPLATIN | Other | — | INFUSION | 30 | 6 | SUB07483MIG |
Abraxane 5 mg/ml powder for dispersion for infusion. | Other | POWDER FOR DISPERSION FOR INFUSION | INFUSION | 125 | 6 | PRD9254301 |
SIMVASTATIN | Test | — | ORAL | 20 | 6 | SUB10529MIG |
CAPECITABINE | Other | — | ORAL | 1250 | 6 | SUB12474MIG |
VALPROIC ACID | Test | — | ORAL | 1500 | 6 | SUB00015MIG |
GEMCITABINE | Other | — | INFUSION | 1000 | 6 | SUB07892MIG |