Valproic Acid/Simvastatin Plus Gemcitabine/Nab-paclitaxel Based Regimens in Untreated Metastatic Pancreatic Adenocarcinoma Patients
- Conditions
- Interventions
- Registration Number
- NCT05821556
- Lead Sponsor
- National Cancer Institute, Naples
- Brief 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).
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Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 240
- 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).
- 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.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Standard Gemcitabine 1000 mg 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). Standard Nab paclitaxel 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). Experimental Simvastatin 20mg 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. Experimental Gemcitabine 1000 mg 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. Experimental Nab paclitaxel 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. Standard Cisplatin 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). Experimental Valproic acid 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. Standard Capecitabine 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). Experimental Cisplatin 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. Experimental Capecitabine 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 Outcome Measures
Name Time Method 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
Name Time Method 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 ...
Quality of Life (QoL) 40 months 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
Trial Locations
- Locations (5)
Università vita e Salute, IRCCS San Raffaele
🇮🇹Milano, Italy
Istituto Nazionale Tumori di Napoli - IRCCS - Fondazione G. Pascale
🇮🇹Napoli, Italy
University of Verona Hospital Trust
🇮🇹Verona, Italy
Università Cattolica Del Sacro Cuore, IRCCS Fondazione Policlinico Universitario Gemelli - Medical Oncology, Roma, Italia
🇮🇹Roma, Italy
Ramon y Cajal Hospital and Health Research Institute (IRYCIS)
🇪🇸Madrid, Spain