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

National Cancer Institute, Naples

Status and phase: Enrolling; Phase 2

Conditions: Adenocarcinoma of the Pancreas

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

Study type: Interventional

Funder types: Other

Identifiers

NCT05821556

1/23 (Other Identifier)

VESPA

Details and patient eligibility

About

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

Full description

The study hypothesizes that valproic acid (VPA) in combination with simvastatin (SIM) may improve the efficacy of first-line gemcitabine and nab-paclitaxel-based regimens and extend progression free survival (PFS) as compared with chemotherapy alone, in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC).

Correlative studies on tumor and blood samples could identify potential biomarkers of toxicity and efficacy helping to define personalized treatment strategy and adding new insight into the antitumor mechanism of the combination approach.

Enrollment: 240 estimated patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion criteria

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 PDAC
4. Either sex aged ≥ 18 years.
5. Eastern Cooperative Oncology Group (ECOG) Performance Status ≤1 at study entry.
6. Imaging-documented measurable disease, according to RECIST 1.1 criteria.
7. Known dihydropyrimidine dehydrogenase (DPD) activity is mandatory for patients enrolled in PAXG scheme.
8. 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.
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 (ALT) ≤ 5 X ULN.
10. 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

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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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240 participants in 2 patient groups

Standard

Active Comparator group

Description:

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).

Treatment:

Drug: Capecitabine

Drug: Cisplatin

Drug: Gemcitabine 1000 mg

Drug: Nab paclitaxel

Experimental

Experimental group

Description:

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.

Treatment:

Drug: Capecitabine

Drug: Cisplatin

Drug: Gemcitabine 1000 mg

Drug: Nab paclitaxel

Drug: Valproic acid

Drug: Simvastatin 20mg