Valproic Acid/Simvastatin Plus Gemcitabine/Nab-paclitaxel... | NCT05821556

ID	Type	Description	Link
1/23	Other Identifier	IRCCS I.N.T. "G. Pascale"

Status Module

Description Module

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
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

Name	Type	Description	Arm Group Labels	Other Names
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.

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
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

Measure	Description	Time Frame
Objective Tumor Response Rate (ORR)	Objective Tumor Response Rate (ORR) as defined by RECIST 1.1, calculated as the proportion of patients achieving complete or partial response relative to total enrolled patients.	40 months
Duration of Objective response (DOR)

Eligibility Module

Eligibility 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 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).

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 (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.

Name	Role	Phone	Extension	Email
Antonio Avallone	Contact	08117770357		a.avallone@istitutotumori.na.it
Alessandra Leone	Contact	08117770585		a.leone@istitutotumori.na.it

Name	Affiliation	Role
Alfredo Budillon	IRCCS I.N.T. "G. Pascale	Principal Investigator
Antonio Avallone	IRCCS I.N.T. "G. Pascale	Principal Investigator

Facility	Status	City	State	ZIP	Country	Contacts
Istituto Nazionale Tumori di Napoli - IRCCS - Fondazione G. Pascale	Recruiting	Naples	Italy	80131	Italy

References Module

Citations

PubMed Identifier	Type	Citation	Retractions
39300376	Derived	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.

ID	Term
D009362	Neoplasm Metastasis

ID	Term
D009385	Neoplastic Processes
D009369	Neoplasms
D010335	Pathologic Processes
D013568	Pathological Conditions, Signs and Symptoms

ID	Term
D014635	Valproic Acid
D019821	Simvastatin
D000093542	Gemcitabine
D013660	Taxes
D002945	Cisplatin
D000069287	Capecitabine

Ancestor Terms

ID	Term
D010421	Pentanoic Acids
D014631	Valerates
D000144	Acids, Acyclic
D002264	Carboxylic Acids
D009930	Organic Chemicals
D005232	Fatty Acids, Volatile
D005227	Fatty Acids
D008055	Lipids
D008148	Lovastatin
D009281	Naphthalenes
D011084	Polycyclic Aromatic Hydrocarbons
D006841	Hydrocarbons, Aromatic
D006844	Hydrocarbons, Cyclic
D006838	Hydrocarbons
D011083	Polycyclic Compounds
D006571	Heterocyclic Compounds
D003841	Deoxycytidine
D003562	Cytidine
D011741	Pyrimidine Nucleosides
D011743	Pyrimidines
D006573	Heterocyclic Compounds, 1-Ring
D004467	Economics
D004472	Health Care Economics and Organizations
D017606	Chlorine Compounds
D007287	Inorganic Chemicals
D017672	Nitrogen Compounds
D017671	Platinum Compounds
D005472	Fluorouracil
D014498	Uracil
D011744	Pyrimidinones
D003853	Deoxyribonucleosides
D009705	Nucleosides
D009706	Nucleic Acids, Nucleotides, and Nucleosides