The aim ot the study is to investigate the efficacy and safety of two new intensified chemotherapy regimens (gemcitabine (Gem)/nab- paclitaxel (PAC), FOLFIRINOX) as neoadjuvant chemotherapy protocol in locally advanced, non-metastatic pancreatic cancer (LAPC) and consecutive conversion of the tumor to resectability.
This is a prospective open randomized multicenter phase II trial with two arms. Patients suffering from histologically confirmed LAPC (and assessed as unresectable or borderline resectable according to National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines "pancreatic adenocarcinoma" version 1.2013) without metastases will receive two different neoadjuvant treatment regimens: First all patients receive two cycles Gem/nab-PAC (duration of each cycle 28 days) as neoadjuvant chemotherapy in equal measure and a first restaging is performed after these two cycles based on imaging criteria. If there is no progression according to Response evaluation criteria in solid tumors (RECIST 1.1) criteria at the first restaging, the patients are randomized in a 1:1 relation to: Two further cycles Gem/nab-PAC (duration of each cycle 28 days). or Four further cycles FOLFIRINOX (duration of each cycle 14 days). After the neoadjuvant chemotherapy a 2nd restaging is performed based on imaging criteria. All patients without progression at this restaging or at an earlier time point undergo obligatory exploratory laparotomy irrespective of imaging criteria to assess resectability. If they are evaluated as converted to resectable during this exploratory laparotomy, pancreas resection in curative intent will be performed. All patients with successful R0 or R1 pancreatic resection will receive three further cycles adjuvant chemotherapy with Gem/nab-PAC. Adjuvant chemotherapy will start within 4 to 8 weeks after pancreatic resection surgery. Further treatment of patients with PD after 1st or 2nd restaging as well as patients with unresectable status based on exploratory laparotomy is under the discretion of the local investigators (e.g. second-line chemotherapy in case of distant relapse or local radiochemotherapy in case of local progression or definitive irresectability). All patients are followed up for local recurrence, progression and survival until death or for at least one year after last application of study drugs whichever is sooner. The translational research conducts exploratory analyses for potential biomarkers of possible prognostic or predictive value for efficacy of neoadjuvant chemotherapy in LAPC; including analyses of circulating tumor cells, molecular pathways of pancreatic adenocarcinoma including SPARC expression.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
168
All patient receive: 2 cycles gemcitabine/nab-paclitaxel (\[Gem/nab-Pac\]; duration of each cycle 28 days) Then: Nab-paclitaxel 125 mg/m2, IV infusion over 30 minutes, followed by gemcitabine 1000 mg/m2 as a 30-minute IV infusion on D1, D8, D15 of each 28-day cycle
All patient receive: 2 cycles gemcitabine/nab-paclitaxel (\[Gem/nab-Pac\]; duration of each cycle 28 days) Then: Oxaliplatin 85 mg/m2, given as a 2-hour intravenous infusion D1 Folinic acid 400 mg/m2, given as a 2-hour intravenous infusion D1 Irinotecan 180 mg/m2, given as a 90-minutes intravenous infusion D1 (application through a Y-connector parallel to infusion of folinic acid or 30 minutes after start of folinic acid possible) Fluorouracil 400 mg/m2, administered by intravenous bolus, followed by a continuous intravenous infusion of fluorouracil 2400 mg/m2 over a 46-hour period D1. To be repeated on D1 of each cycle.
Universitätsklinikum Würzburg/Comprehensive Cancer Center Mainfranken
Würzburg, Bavaria, Germany
Conversion Rate
To compare the effect of intensified neoadjuvant chemotherapy on conversion rate to resectability in LAPC.
Time frame: approx. 10 month
Safety
evaluate safety and tolerability of intensified neoadjuvant chemotherapy * Exposure to study drugs * Type, incidence, and severity of adverse events * Dose reduction or discontinuation of study drugs due to adverse events * Laboratory parameters
Time frame: approx. 22 month
objective tumour response rate
assess objective tumour response rate (ORR) to intensified neoadjuvant chemotherapy Baseline tumor measurement(s) will be performed within 4 weeks before the first dose of study drug with either computed tomography (CT) including spiral CT or MRI according to investigator's choice and clinical practice at the respective trial site as done routinely also outside of clinical trial situations.The same method used at baseline must be used consistently for response assessment to neoadjuvant chemotherapy at the first restaging (after the first part of neoadjuvant chemotherapy) and the second restaging (after the second part of neoadjuvant chemotherapy) and thereafter.
Time frame: approx. 22 month
disease control rate (DCR)
assess disease control rate (DCR) after intensified neoadjuvant chemotherapy
Time frame: approx. 22 month
CA 19-9 change
Assess carbohydrate antigen 19-9 (CA 19-9) change during/after neoadjuvant chemotherapy. In this trial, CA 19-9 change to neoadjuvant chemotherapy will be evaluated as decrease to the baseline level at the 1st and 2nd restaging.
Time frame: 10 month
R0 and R1 resections
This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.
assess rate of R0 and R1 resections
Time frame: 10 month
pathological responses
assess rate of grade 3 + 4 pathological responses according to grading scheme of treatment responses by Evans in resected patients.
Time frame: approx. 22 month
relapse-free survival (RFS)
assess relapse-free survival (RFS): Relapse-free survival is the time from Day 1 after pancreatic resection to the date of relapse, defined as Day 1 after pancreatic resection to either local relapse of pancreatic cancer or occurrence of distant metastases. For each patient who is not known to have had a relapse as of the data-inclusion cut-off date for a particular analysis, time to relapse will be censored for that analysis at the date of the patient's last study visit prior to that cut-off date.
Time frame: approx. 22 month
Progression-free survival (PFS)
PFS is the time from Day 1 of the first cycle of neoadjuvant chemotherapy to date of objective disease progression or to death of any cause. For each patient who is not known to have had a progression as of the data-inclusion cut-off date for a particular analysis, time to progressive disease will be censored for that analysis at the date of the patient's last study visit prior to that cut-off date.
Time frame: approx. 2 years
perioperative morbidity and mortality
assess perioperative morbidity and mortality
Time frame: 60 days
Tolerability
evaluate safety and tolerability of intensified neoadjuvant chemotherapy (see safety measure)
Time frame: 10 month
Overall Survival (OS)
OS is the time from Day 1 of the first cycle of neoadjuvant chemotherapy to date of death from any cause. The rate of patients who have died from any cause after one year and two years, respectively will be assessed. For each patient for whom it is not known whether he died or is still alive until the data-inclusion cut-off date for a particular analysis, time to death of any cause will be censored for that analysis at the date of the patient's last study visit prior to that cut-off date.
Time frame: approx. 22 month