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)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

IRCCS Istituto Nazionale Tumori Fondazione Pascale

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

12 Jun 2023 → ongoing

Decision date (initial)

2024-11-19

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Ministero della Salute (progetto RF-2021-12371995) · Remedi4All EU project (Project number: 101057442; HORIZON-HLTH-2021-DISEASE-04-02)

External identifiers

EU CT number

2024-518710-11-00

EudraCT number

2022-004154-63

ClinicalTrials.gov

NCT05821556

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy

To test whether the combination of valproic acid and simvastatin plus gemcitabine/nabpaclitaxel- based regimens (AG or PAXG) may improve the efficacy of first-line gemcitabine and nab-paclitaxel-based regimens in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC).

Secondary objectives 2

1. To explore the feasibility, the efficacy and the safety of this novel combined approach in first-line mPDAC patients and the impact on their quality of life. Correlative studies on tumor and blood samples could identify potential biomarkers of toxicity/efficacy also adding new insight into the antitumor mechanism of VPA/SIM in combination with chemotherapy.
2. Correlative studies on tumor and blood samples could identify potential biomarkers of toxicity/efficacy also adding new insight into the antitumor mechanism of VPA/SIM in combination with chemotherapy.

Conditions and MedDRA coding

Metastatic pancreatic ductal adenocarcinoma (mPDAC)

Study design 1 period

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 9

1. Written informed consent to study procedures and to correlative studies.
2. Histologically or cytologically proven metastatic PDAC
3. No prior treatments (chemotherapy, radiation or surgery) for mPDAC
4. Eastern Cooperative Oncology Group (ECOG) Performance Status ≤1 at study entry.
5. Imaging-documented measurable disease, according to RECIST 1.1 criteria.
6. Either sex aged ≥ 18
7. Known dihydropyrimidine dehydrogenase (DPD) activity is mandatory for patients enrolled in PAXG scheme
8. 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
9. 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 15

1. 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.
2. Prior chemotherapy or any other medical treatment for metastatic PDAC (previous adjuvant chemotherapy is allowed if terminated > 6 months previously).
3. 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.
4. Current use of statins or fibrates or any medication for hypercholesterolemia for any time during the 3 months before the study.
5. Proven hypersensitivity to statins and to any component of the other medications used in the trial.
6. Major surgical intervention within 4 weeks prior to enrollment.
7. Pregnancy and breast-feeding.
8. Brain metastasis
9. Hepatitis or any severe liver disorder
10. 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.
11. Patients with long QT-syndrome or QTc interval duration > 480 msec or concomitant medication with drugs prolonging QTc
12. 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
13. Participation in any interventional drug study within 30 days prior to treatment start.
14. Patients who cannot take oral medication, who require intravenous alimentation, have had prior surgical procedures affecting absorption, or have active peptic ulcer disease
15. Sexually active males and females (of childbearing potential) unwilling to practice contraception during the study and until 6 months after the last trial treatment.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Progression Free Survival (PFS) between two arms 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.

Secondary endpoints 3

1. To compare the two 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 • Quality of life (QoL)
2. To evaluate mechanistically–based pharmacokinetic and pharmacodynamic biomarkers on blood samples.
3. To explore prognostic factors and predictive biomarkers for response and toxicity on blood samples as well as primary tumors and resected metastases when available

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 3

Auxiliary 4

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

IRCCS Istituto Nazionale Tumori Fondazione Pascale

Sponsor organisation

IRCCS Istituto Nazionale Tumori Fondazione Pascale

Address

Via Mariano Semmola 52

City

Naples

Postcode

80131

Country

Italy

Scientific contact point

Organisation

IRCCS Istituto Nazionale Tumori Fondazione Pascale

Contact name

Alfredo Budillon

Public contact point

Organisation

IRCCS Istituto Nazionale Tumori Fondazione Pascale

Contact name

Alfredo Budillon

Locations

2 EU/EEA countries · 14 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 40 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

4 submissions — initial application plus substantial / non-substantial modifications