Valproic Acid combinEd With Simvastatin and Gemcitabine/Nab-paclitaxel-based Regimens in Untreated Metastatic Pancreatic Adenocarcinoma Patients.

Sponsor

National Cancer Institute, Naples (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT05821556

Collaborator

(none)

240

Enrollment

Locations

Arms

Anticipated Duration (Months)

Patients Per Site

1.3

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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

Condition or Disease	Intervention/Treatment	Phase
Adenocarcinoma of the Pancreas	Drug: Valproic acid Drug: Simvastatin 20mg Drug: Gemcitabine 1000 mg Drug: Nab paclitaxel Drug: PAXG	Phase 2

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

240 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

Patients will be randomized electronically 1:1 to one of the two arms: A. Standard: 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). B. 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.Patients will be randomized electronically 1:1 to one of the two arms:Standard: 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). B. 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.

Masking:

None (Open Label)

Primary Purpose:

Treatment

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).

Anticipated Study Start Date :

May 1, 2023

Anticipated Primary Completion Date :

Aug 1, 2025

Anticipated Study Completion Date :

Jun 1, 2026

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Standard 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 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. 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, 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. Drug: PAXG 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.
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 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. 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, 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. 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, 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. 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, 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. Drug: PAXG 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.

Arm

Intervention/Treatment

Active Comparator: Standard

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

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.

Drug: Nab paclitaxel

Drug: PAXG

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: PAXG

Outcome Measures

Primary Outcome Measures

Progression Free Survival (PFS) [40 months]
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 Outcome Measures

Objective Tumor Response Rate (ORR) [40 months]
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.
Duration of Objective response (DOR) [40 months]
Duration of Objective response (DOR) defined as the first occurrence of a documented objective response until progression or death for any cause.
Disease Control Rate (DCR) [40 months]
Disease Control Rate (DCR) defined as the proportion of patients with complete/partial response and stable disease as their best response.
Overall Survival (OS) [40 months]
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.
Overall toxicity rate [40 months]
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.
Quality of Life (QoL) [40 months]
Quality of Life (QoL), based on questionnaire EORTC QLQ-C30 and QLQ-PAN26 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.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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 PDCA (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.
Major surgical intervention within 4 weeks prior to enrollment;
Pregnancy and breast-feeding.
Brain metastasis.
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 (barrier contraceptive measure or oral contraception) during the study and until 6 months after the last trial treatment.

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	Università vita e Salute, IRCCS San Raffaele	Milano	Italy
2	Istituto Nazionale Tumori di Napoli - IRCCS - Fondazione G. Pascale	Napoli	Italy	80131
3	Università Cattolica Del Sacro Cuore, IRCCS Fondazione Policlinico Universitario Gemelli - Medical Oncology, Roma, Italia	Roma	Italy
4	University of Verona Hospital Trust	Verona	Italy	37122
5	Ramon y Cajal Hospital and Health Research Institute (IRYCIS)	Madrid	Spain