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

Official title

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

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

Detailed 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.

Interventions

• Drug Valproic acid
  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, w
• Drug Simvastatin 20mg
  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, w
• Drug Gemcitabine 1000 mg
  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, w
• Drug Nab paclitaxel
  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, w
• Drug Cisplatin
  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, w
• Drug Capecitabine
  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, w

Primary outcome measures

• Progression Free Survival (PFS) [Time frame: 40 months]

Secondary outcome measures (6)

• Objective Tumor Response Rate (ORR) [Time frame: 40 months]
• Duration of Objective response (DOR) [Time frame: 40 months]
• Disease Control Rate (DCR) [Time frame: 40 months]
• Overall Survival (OS) [Time frame: 40 months]
• Overall toxicity rate [Time frame: 40 months]
• Quality of Life (QoL) [Time frame: 40 months]

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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

Italy · 4 centers

• Istituto Nazionale Tumori di Napoli - IRCCS - Fondazione G. Pascale — Naples
• Università vita e Salute, IRCCS San Raffaele — Milan
• Università Cattolica Del Sacro Cuore, IRCCS Fondazione Policlinico Universitario Gemelli - — Roma
• University of Verona Hospital Trust — Verona

Spain · 1 center

• Ramon y Cajal Hospital and Health Research Institute (IRYCIS) — Madrid

Publications

• 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 adenocarc PMID 39300376

Identifiers

NCT: NCT05821556 · VESPA · 1/23

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗