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

Adenocarcinoma of the Pancreas Clinical Trial

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).

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05821556
• Other study ID #: VESPA
• Secondary ID: 1/23
• Status: Recruiting
• Phase: Phase 2
• Start date: June 12, 2023
• Est. completion date: June 2026

Study information

• Verified date: May 2024
• Source: National Cancer Institute, Naples
• Contact: Antonio Avallone
• Phone: 08117770357
• Email: a.avallone[@]istitutotumori.na.it
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 240
• Est. completion date: June 2026
• Est. primary completion date: August 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Adenocarcinoma
• Adenocarcinoma of the Pancreas

Intervention

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, 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.
• 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, 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.
• 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, 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.
• 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, 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.
• 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, 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.
• 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, 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.

Locations

Country	Name	City	State
Italy	Università vita e Salute, IRCCS San Raffaele	Milano
Italy	Istituto Nazionale Tumori di Napoli - IRCCS - Fondazione G. Pascale	Napoli
Italy	Università Cattolica Del Sacro Cuore, IRCCS Fondazione Policlinico Universitario Gemelli - Medical Oncology, Roma, Italia	Roma
Italy	University of Verona Hospital Trust	Verona
Spain	Ramon y Cajal Hospital and Health Research Institute (IRYCIS)	Madrid

Sponsors (1)

Lead Sponsor	Collaborator
National Cancer Institute, Naples

Countries where clinical trial is conducted

Italy,  Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	Duration of Objective response (DOR)	Duration of Objective response (DOR) defined as the first occurrence of a documented objective response until progression or death for any cause.	40 months
Secondary	Disease Control Rate (DCR)	Disease Control Rate (DCR) defined as the proportion of patients with complete/partial response and stable disease as their best response.	40 months
Secondary	Overall Survival (OS)	Overall Survival (OS) defined as the time from randomization to the date of death due to any cause. OS will be censored at the last date the patient was known to be alive for patients alive at the time of analysis.	40 months
Secondary	Overall toxicity rate	Overall toxicity rate defined as the proportion of patients experiencing any grade AE accordingly to the NCI Common Terminology Criteria of Adverse Events (NCI CTC-AE) Version 5, relative to the total of patients receiving at least one cycle of treatment.AE will be listed individually by the patient and summarized overall (severity grades 1-4) and for grade =3 by treatment received.	40 months
Secondary	Quality of Life (QoL)	Quality of Life (QoL), based on questionnaire EORTC QLQ-C30 at baseline (prior to treatment start, once eligibility is confirmed) and every 8 weeks until 40 weeks after randomization, regardless of disease progression, or death	40 months