THE (COST)EFFECTIVENESS OF NEOADJUVANT FOLFIRINOX VERSUS NEOADJUVANT GEMCITABINE BASED CHEMORADIOTHERAPY AND ADJUVANT GEMCITABINE FOR (BORDERLINE) RESECTABLE PANCREATIC CANCER

INTERVENTION: Trade Name: LEUCOVORIN CALCIUM Product Name: Leucovorin calcium Pharmaceutical Form: Powder for solution for injection/infusion INN or Proposed INN: Calcium folinate CAS Number: 1492‐18‐8 Current Sponsor code: leucovorin Other descriptive name: FOLINIC ACID Concentration unit: mg/ml milligram(s)/millilitre Concentration type: equal Concentration number: 400‐ Trade Name: Fluorouracil Product Name: Fluorouracil Pharmaceutical Form: Solution for infusion INN or Proposed INN: Fluorouracil CAS Number: 51‐21‐8 Current Sponsor code: 5‐FU Other descriptive name: FLUOROURACIL Concentration unit: mg/ml milligram(s)/millilitre Concentration type: equal Concentration number: 50‐ Trade Name: Irinotecan Product Name: Irinotecan Pharmaceutical Form: Concentrate for solution for infusion INN or Proposed INN: IRINOTECAN CAS Number: 97682‐44‐5 Current Sponsor code: Irinotecan Concentration unit: mg/ml milligram(s)/millilitre Concentration type: equal Concentration number: 180‐ Trade Name: Oxaliplatin Product Name: Oxaliplatin Pharmaceutical Form: Concentrate for solution for infusion INN or Proposed INN: OXALIPLATIN CAS Number: 61825‐94‐3 Current Sponsor code: Oxaliplatin Other descriptive name: Oxaliplatin Concentration unit: mg/m2 milligram(s)/square meter Concentration type: equal Concentration number: 85‐ CONDITION: (borderline) resectable pancreatic cancer ; MedDRA version: 21.0 Level: LLT Classification code 10033602 Term: Pancreatic adenocarcinoma resectable System Organ Class: 100000004864 Therapeutic area: Diseases [C] ‐ Cancer [C04] PRIMARY OUTCOME: Main Objective: To determine whether neoadjuvant FOLFIRINOX followed by surgery improves overall survival compared to neoadjuvant chemoradiotherapy followed by surgery and adjuvant gemcitabine in patients with (borderline) resectable pancreatic cancer in an intention‐to‐treat setting. Primary end point(s): • Overall survival (OS), defined as the period of time between randomization and death from any cause. Patients alive at last follow‐up are censored. Secondary Objective: To compare between the study arms:; • Chemotherapy rate; • Chemotherapy completion rate; • Staging laparoscopy rate; • Laparoscopy yield; • Exploratory laparotomy rate; • Resection rate; • R0 resection rate; • Progression‐free survival (PFS); • Locoregional failure free interval (LFFI); • Distant metastases free interval (DMFI); • Postoperative complications; • Toxicity; • Quality of life years (QALYs) ; • Indirect and direct medical and nonmedical costs ; • Incremental cost‐effectiveness ratio (ICER) ; • Predictive value of biomarkers in serum and resected tumors.; • Disease free survival (DFS); • Locoregional recurrence free interval (LRFI); • Clinical response rate ; • Serum Cancer Antigen 19‐9 (CA 19.9) and Carcino‐Embryonal‐Antigen (CEA) response; • Pathologic response Timepoint(s) of evaluation of this end point: end of study INCLUSION CRITERIA: • Histologically or cytologically confirmed pancreatic cancer (i.e. pancreatic ductal adenocarcinoma) • (Borderline) resectable tumor without metastatic disease* (see table 1 for definitions of resectability) • WHO performance status 0 or 1 • Ability to undergo surgery, chemoradiotherapy and chemotherapy** • Leucocytes (WBC) = 3.0 X 109/l • Platelets = 100X 109 /l • Hemoglobin = 6 mmol/l • Renal function: E‐GFR = 50 ml/min • Age = 18 years • Written informed consent Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18‐64 years) yes F.1.2.1 Number of subjects for this age range 300 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 68 SECONDARY OUTCOME: Secondary end point(s): • Chemotherapy rate, defined as the percentage of eligible randomized patients who received at least one cycle of chemotherapy.; • Chemotherapy completion rate, defined as the percentage of eligible randomized patients who completed all cycles of scheduled chemotherapy.; • Exploratory laparotomy rate, defined as the percentage of eligible randomized patients who actually underwent an exploratory laparotomy, regardless whether a resection was performed.; • Resection rate, defined as the percentage of eligible randomized patients that underwent a curative‐intent resection.; • R0 resection rate, defined as the percentage of eligible randomized patients that underwent a microscopically complete (R0) resection. The resection is considered R0 if the inked margin is more than 1 mm away from tumor cells.; • Progression‐free survival, defined as survival without locoregional progressive disease , the occurence of distant metastases, the occurence of second or recurrent pancreatic cancer from the date of randomization. Death from any cause is also considered an event for this endpoint.; • Locoregional failure free interval (LFFI), defined as the period of time without locoregional failure after randomization. A locoregional failure is any progressive or recurrent pancreatic cancer in the original tumor location, or the N1 lymph node areas, or the occurrence of second pancreatic cancer. ; • Distant metastases free interval (DMFI), defined as the period of time without distant metastases after randomization.; • Postoperative complications, defined according to the Clavien‐Dindo classification and definitions of post‐pancreatic surgery complications (pancreatic fistula, delayed gastric emptying, and bleeding) by the International Study Group on Pancreatic Surgery.; • Toxicity, gastro‐intestinal and hematologic, according to CTCAE version 4.0.3, until 90 days after the last dose of chemotherapy.; • Quality of life years (QALYs) from randomization until last follow‐up.; • Indirect and direct medical and nonmedical costs.; • Incremental cost‐effectiveness ratio (ICER). Is calculated as the ratio between the difference in QALYs and the difference in total costs per patient.; • Predictive value of biomarkers in serum and resected tumors.; • Disease free survival (DFS), defined as the period of time between randomization and locoregional recurrence, occurrence of distant metastases or second pancreatic cancer, or death (all causes).; • Locoregional recurrence free interval (LRFI), defined as the period of time without locoregional recurrence after randomization. A locoregional failure is any persistent or recurrent pancreatic cancer in the original tumor location, or the N1 lymph node areas.; • Clinical response rate defined according to RECIST criteria (version 1.1) comparing pre‐randomization and restaging imaging after preoperative chemoradiotherapy and after 4 and 8 cycles of FOLFIRINOX.; • Serum CA 19‐9 and CEA response, defined as the change in CA 19‐9 and CEA after preoperative chemoradiotherapy and after 4 and 8 cycles of FOLFIRINOX compared to baseline.; • Pathologic response, 3‐tier histologic tumor regression grading (HTRG) scheme proposed by the College of American Pathologists; HTRG 0, no viable tumor; HTRG 1, <5% viable tumor cells; HTRG 2, =5% viable tumor cells. ; ; Timepoint(s) of evaluation of this end point: end of study