Valproic Acid/Simvastatin Plus Gemcitabine/Nab-paclitaxel Based Regimens in Untreated Metastatic Pancreatic Adenocarcinoma Patients

NCT05821556 | Recruiting Phase 2 DMC

• 2 other identifiers: VESPA1/23
• Study Type: interventional
• Target: 240
• Locations: 2 countries
• Sites: 5

Brief Summary

This is a proof-of-concept, Open label, randomized, multicentric, superiority phase-2 study.

Conditions

Adenocarcinoma of the Pancreas

Keywords

Metastatic

Outcome Measures

Primary Outcomes (1)

• Progression Free Survival (PFS)

  PFS is defined as the time from randomization to the first documentation of objective disease progression by 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 absence of progressive disease for patients alive at the time of analysis.

  40 months

Secondary Outcomes (6)

• Objective Tumor Response Rate (ORR)

  40 months

• Duration of Objective response (DOR)

  40 months

• Disease Control Rate (DCR)

  40 months

• Overall Survival (OS)

  40 months

• Overall toxicity rate

  40 months

Study Arms (2)

Standard

ACTIVE COMPARATOR

Nab-paclitaxel 125 mg/m2 followed by gemcitabine 1000 mg/m2 on days 1, 8, and 15 (AG); or nab-paclitaxel 150 mg/m2, followed by gemcitabine 800 mg/m2, followed by cisplatin 30 mg/m2 on days 1 and 15, and oral capecitabine 1250 mg/m2 on days 1-28 (PAXG).

Drug: Gemcitabine 1000 mg; Drug: Nab paclitaxel; Drug: Cisplatin; Drug: Capecitabine

Experimental

EXPERIMENTAL

Chemotherapy (AG or PAXG) + simvastatin oral daily at a fixed dosage of 20 mg in combination with increasing doses of valproic acid administered oral daily from day -7 with an intra-patient titration for a final target serum level of 50-100µg/ml.

Drug: Valproic acid; Drug: Simvastatin 20mg; Drug: Gemcitabine 1000 mg; Drug: Nab paclitaxel; Drug: Cisplatin; Drug: Capecitabine

Interventions

Valproic acid DRUG

The treatment should be started within 3 days from randomization. One cycle consisted of 28 days of treatment for both arms. Patients will continue to receive study treatment up to 6 cycles until disease progression, unacceptable toxicity, physician's decision, patient's refusal, or any other discontinuation criteria. Continuation of treatment, over the six cycles, will be allowed only in case of clinical benefit, defined as continuous decrease of CA19-9 concentration or radiological response, without unacceptable toxicity. All subjects who finish treatment, whichever the reason, will enter in the follow-up. We expect that for the primary endpoint, PFS, follow-up will last up to 10 months after enrollment. Anyhow, all subjects will be followed until death and data on subsequent treatment will be collected.

Experimental

Simvastatin 20mg DRUG

The treatment should be started within 3 days from randomization. One cycle consisted of 28 days of treatment for both arms. Patients will continue to receive study treatment up to 6 cycles until disease progression, unacceptable toxicity, physician's decision, patient's refusal, or any other discontinuation criteria. Continuation of treatment, over the six cycles, will be allowed only in case of clinical benefit, defined as continuous decrease of CA19-9 concentration or radiological response, without unacceptable toxicity. All subjects who finish treatment, whichever the reason, will enter in the follow-up. We expect that for the primary endpoint, PFS, follow-up will last up to 10 months after enrollment. Anyhow, all subjects will be followed until death and data on subsequent treatment will be collected.

Experimental

Gemcitabine 1000 mg DRUG

The treatment should be started within 3 days from randomization. One cycle consisted of 28 days of treatment for both arms. Patients will continue to receive study treatment up to 6 cycles until disease progression, unacceptable toxicity, physician's decision, patient's refusal, or any other discontinuation criteria. Continuation of treatment, over the six cycles, will be allowed only in case of clinical benefit, defined as continuous decrease of CA19-9 concentration or radiological response, without unacceptable toxicity. All subjects who finish treatment, whichever the reason, will enter in the follow-up. We expect that for the primary endpoint, PFS, follow-up will last up to 10 months after enrollment. Anyhow, all subjects will be followed until death and data on subsequent treatment will be collected.

Experimental; Standard

Nab paclitaxel DRUG

The treatment should be started within 3 days from randomization. One cycle consisted of 28 days of treatment for both arms. Patients will continue to receive study treatment up to 6 cycles until disease progression, unacceptable toxicity, physician's decision, patient's refusal, or any other discontinuation criteria. Continuation of treatment, over the six cycles, will be allowed only in case of clinical benefit, defined as continuous decrease of CA19-9 concentration or radiological response, without unacceptable toxicity. All subjects who finish treatment, whichever the reason, will enter in the follow-up. We expect that for the primary endpoint, PFS, follow-up will last up to 10 months after enrollment. Anyhow, all subjects will be followed until death and data on subsequent treatment will be collected.

Experimental; Standard

Cisplatin DRUG

The treatment should be started within 3 days from randomization. One cycle consisted of 28 days of treatment for both arms. Patients will continue to receive study treatment up to 6 cycles until disease progression, unacceptable toxicity, physician's decision, patient's refusal, or any other discontinuation criteria. Continuation of treatment, over the six cycles, will be allowed only in case of clinical benefit, defined as continuous decrease of CA19-9 concentration or radiological response, without unacceptable toxicity. All subjects who finish treatment, whichever the reason, will enter in the follow-up. We expect that for the primary endpoint, PFS, follow-up will last up to 10 months after enrollment. Anyhow, all subjects will be followed until death and data on subsequent treatment will be collected.

Experimental; Standard

Capecitabine DRUG

The treatment should be started within 3 days from randomization. One cycle consisted of 28 days of treatment for both arms. Patients will continue to receive study treatment up to 6 cycles until disease progression, unacceptable toxicity, physician's decision, patient's refusal, or any other discontinuation criteria. Continuation of treatment, over the six cycles, will be allowed only in case of clinical benefit, defined as continuous decrease of CA19-9 concentration or radiological response, without unacceptable toxicity. All subjects who finish treatment, whichever the reason, will enter in the follow-up. We expect that for the primary endpoint, PFS, follow-up will last up to 10 months after enrollment. Anyhow, all subjects will be followed until death and data on subsequent treatment will be collected.

Experimental; Standard

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Written informed consent to study procedures and to correlative studies.
• Histologically or cytologically proven metastatic PDAC.
• No prior treatments (chemotherapy, radiation or surgery) for PDAC
• Either sex aged ≥ 18 years.
• Eastern Cooperative Oncology Group (ECOG) Performance Status ≤1 at study entry.
• Imaging-documented measurable disease, according to RECIST 1.1 criteria.
• Known dihydropyrimidine dehydrogenase (DPD) activity is mandatory for patients enrolled in PAXG scheme.
• Adequate bone marrow haematological function: absolute neutrophil count (ANC) ≥ 1.5 x 109/L AND platelet count ≥ 100 x 109/L AND 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 (ALT) ≤ 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).

You may not qualify if:

• 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 (see list in the appendix).
• 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 or medical device 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.

Sponsors & Collaborators

• National Cancer Institute, Naples: lead

Study Sites (5)

Istituto Nazionale Tumori di Napoli - IRCCS - Fondazione G. Pascale

Naples, Italy, 80131, Italy

RECRUITING

Università vita e Salute, IRCCS San Raffaele

Milan, Milano, Italy

RECRUITING

Università Cattolica Del Sacro Cuore, IRCCS Fondazione Policlinico Universitario Gemelli - Medical Oncology, Roma, Italia

Roma, Roma, Italy

RECRUITING

University of Verona Hospital Trust

Verona, Verona, 37122, Italy

RECRUITING

Ramon y Cajal Hospital and Health Research Institute (IRYCIS)

Madrid, Madrid, Spain

RECRUITING

Related Publications (1)

• Budillon A, Leone A, Passaro E, Silvestro L, Foschini F, Iannelli F, Roca MS, Macchini M, Bruzzese F, Garcia Bermejo ML, Rodriguez Garrote M, Tortora G, Milella M, Reni M, Fuchs C, Hewitt E, Kubiak C, Di Gennaro E, Giannarelli D, Avallone A. 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. BMC Cancer. 2024 Sep 19;24(1):1167. doi: 10.1186/s12885-024-12936-w.

  PMID: 39300376 DERIVED

MeSH Terms

Conditions

Neoplasm Metastasis

Interventions

Valproic Acid; Simvastatin; Gemcitabine; Taxes; Cisplatin; Capecitabine

Condition Hierarchy (Ancestors)

Neoplastic Processes; Neoplasms; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Pentanoic Acids; Valerates; Acids, Acyclic; Carboxylic Acids; Organic Chemicals; Fatty Acids, Volatile; Fatty Acids; Lipids; Lovastatin; Naphthalenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Polycyclic Compounds; Heterocyclic Compounds; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Economics; Health Care Economics and Organizations; Chlorine Compounds; Inorganic Chemicals; Nitrogen Compounds; Platinum Compounds; Fluorouracil; Uracil; Pyrimidinones; Deoxyribonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides

Study Officials

• Alfredo Budillon

  IRCCS I.N.T. "G. Pascale

  PRINCIPAL INVESTIGATOR

• Antonio Avallone

  IRCCS I.N.T. "G. Pascale

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Antonio Avallone

CONTACT

08117770357; a.avallone@istitutotumori.na.it

Alessandra Leone

CONTACT

08117770585; a.leone@istitutotumori.na.it

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Patients will be randomized electronically 1:1 to one of the two arms: A. Standard: Nab-paclitaxel 125 mg/m2 followed by gemcitabine 1000 mg/m2 on days 1, 8, and 15 (AG); or nab-paclitaxel 150 mg/m2, followed by gemcitabine 800 mg/m2, followed by cisplatin 30 mg/m2 on days 1 and 15, and oral capecitabine 1250 mg/m2 on days 1-28 (PAXG). B. Experimental: Chemotherapy (AG or PAXG) + simvastatin oral daily at a fixed dosage of 20 mg in combination with increasing doses of valproic acid administered oral daily from day -7 with an intra-patient titration for a final target serum level of 50-100µg/ml.

Study Record Dates

• First Submitted: March 23, 2023
• First Posted: April 20, 2023
• Study Start: June 12, 2023
• Primary Completion (Estimated): August 1, 2026
• Study Completion (Estimated): June 1, 2027
• Last Updated: April 14, 2026

Record last verified: 2025-07

Locations

IT (4); ES (1)