Trial Title:
Valproic Acid/Simvastatin Plus Gemcitabine/Nab-paclitaxel Based Regimens in Untreated Metastatic Pancreatic Adenocarcinoma Patients
NCT ID:
NCT05821556
Condition:
Adenocarcinoma of the Pancreas
Conditions: Official terms:
Adenocarcinoma
Paclitaxel
Gemcitabine
Capecitabine
Valproic Acid
Simvastatin
Conditions: Keywords:
Metastatic
Study type:
Interventional
Study phase:
Phase 2
Overall status:
Recruiting
Study design:
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.
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
Valproic acid
Description:
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 group label:
Experimental
Intervention type:
Drug
Intervention name:
Simvastatin 20mg
Description:
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 group label:
Experimental
Intervention type:
Drug
Intervention name:
Gemcitabine 1000 mg
Description:
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 group label:
Experimental
Arm group label:
Standard
Intervention type:
Drug
Intervention name:
Nab paclitaxel
Description:
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 group label:
Experimental
Arm group label:
Standard
Intervention type:
Drug
Intervention name:
Cisplatin
Description:
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 group label:
Experimental
Arm group label:
Standard
Intervention type:
Drug
Intervention name:
Capecitabine
Description:
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 group label:
Experimental
Arm group label:
Standard
Summary:
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.
Criteria for eligibility:
Criteria:
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.
Gender:
All
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
Università vita e Salute, IRCCS San Raffaele
Address:
City:
Milano
Country:
Italy
Status:
Recruiting
Contact:
Last name:
Michele Reni
Phone:
0226437644
Email:
reni.michele@hsr.it
Facility:
Name:
Istituto Nazionale Tumori di Napoli - IRCCS - Fondazione G. Pascale
Address:
City:
Napoli
Zip:
80131
Country:
Italy
Status:
Recruiting
Contact:
Last name:
Antonio Avallone, MD
Phone:
00390815903629
Email:
a.avallone@istitutotumori.na.it
Contact backup:
Last name:
Alfredo Budillon, MD
Phone:
00390815903292
Email:
a.budillon@istitutotumori.na.it
Facility:
Name:
Università Cattolica Del Sacro Cuore, IRCCS Fondazione Policlinico Universitario Gemelli - Medical Oncology, Roma, Italia
Address:
City:
Roma
Country:
Italy
Status:
Recruiting
Contact:
Last name:
Giampaolo Tortora
Phone:
0630157080
Email:
giampaolo.tortora@policlinicogemelli.it
Facility:
Name:
University of Verona Hospital Trust
Address:
City:
Verona
Zip:
37122
Country:
Italy
Status:
Recruiting
Contact:
Last name:
Michele Milella
Phone:
0458128502
Email:
michele.milella@univr.it
Facility:
Name:
Ramon y Cajal Hospital and Health Research Institute (IRYCIS)
Address:
City:
Madrid
Country:
Spain
Status:
Recruiting
Contact:
Last name:
Maria Laura Garcia Bermejo
Phone:
+34914889706
Email:
garciabermejo@gmail.com
Start date:
June 12, 2023
Completion date:
June 2026
Lead sponsor:
Agency:
National Cancer Institute, Naples
Agency class:
Other
Source:
National Cancer Institute, Naples
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT05821556
