Testing the Use of the Usual Chemotherapy Before and After Surgery for Removable Pancreatic Cancer
Testing the Use of the Usual Chemotherapy Before and After Surgery for Removable Pancreatic Cancer
This phase III trial compares perioperative chemotherapy (given before and after surgery)
 versus adjuvant chemotherapy (given after surgery) for the treatment of pancreatic cancer
 that can be removed by surgery (removable/resectable). Chemotherapy drugs, such as
 fluorouracil, irinotecan, leucovorin, and oxaliplatin, work in different ways to stop the
 growth of tumor cells, either by killing the cells, by stopping them from dividing, or by
 stopping them from spreading. Giving chemotherapy before and after surgery (perioperatively)
 may work better in treating patients with pancreatic cancer compared to giving chemotherapy
 after surgery (adjuvantly).
PRIMARY OBJECTIVES:

 I. To evaluate and compare overall survival (OS) in patients with resectable pancreatic
 adenocarcinoma treated with perioperative fluorouracil, irinotecan hydrochloride, leucovorin
 calcium and oxaliplatin (modified [m]FOLFIRINOX) and surgery versus up-front surgery followed
 by adjuvant mFOLFIRINOX.

 SECONDARY OBJECTIVES:

 I. To evaluate and compare disease-free survival (DFS) in patients with resectable pancreatic
 adenocarcinoma treated with perioperative mFOLFIRINOX and surgery versus up-front surgery
 followed by adjuvant mFOLFIRINOX.

 II. To evaluate and compare time to locoregional recurrence (TLR) in patients with resectable
 pancreatic adenocarcinoma treated with perioperative mFOLFIRINOX and surgery versus up-front
 surgery followed by adjuvant mFOLFIRINOX.

 III. To evaluate and compare time to distant metastases (TDM) in patients with resectable
 pancreatic adenocarcinoma treated with perioperative mFOLFIRINOX and surgery versus up-front
 surgery followed by adjuvant mFOLFIRINOX.

 IV. To evaluate and compare the R0 resection rate in patients with resectable pancreatic
 adenocarcinoma treated with perioperative mFOLFIRINOX and surgery versus up-front surgery
 followed by adjuvant mFOLFIRINOX.

 V. To evaluate and compare rate of unresectability in patients with resectable pancreatic
 adenocarcinoma treated with perioperative mFOLFIRINOX and surgery versus up-front surgery
 followed by adjuvant mFOLFIRINOX.

 VI. To evaluate rate of pathologic complete response in patients randomized to the
 perioperative therapy arm.

 VII. To evaluate and compare mFOLFIRINOX dose intensity delivered and number of cycles
 received in patients with resectable pancreatic adenocarcinoma treated with perioperative
 mFOLFIRINOX and surgery versus up-front surgery followed by adjuvant mFOLFIRINOX.

 VIII. To evaluate and compare adverse event profile in patients with resectable pancreatic
 adenocarcinoma treated with perioperative mFOLFIRINOX and surgery versus up-front surgery
 followed by adjuvant mFOLFIRINOX.

 IX. To compare physical functioning, nausea/vomiting, and diarrhea, as measured with the
 European Organization for Research and Treatment of Cancer (EORTC) Quality of Life
 Questionnaire-Core 30 (QLQ-C30) between patients with resectable pancreatic adenocarcinoma
 treated with perioperative mFOLFIRINOX and surgery versus up-front surgery followed by
 adjuvant mFOLFIRINOX.

 X. To prospectively assess the influence of diet, body mass index, weight loss, physical
 activity, and other lifestyle habits on the disease-free survival and overall survival among
 patients with localized pancreatic cancers.

 XI. To assess the influence of diet, obesity, physical activity, and other lifestyle habits
 on the risk of toxicity associated with chemotherapy.

 XII. To evaluate the ability of computed tomography (CT)-based radiomics in distinguishing
 post-neoadjuvant chemotherapy (NAC) fibrosis from viable tumor in patients randomized to the
 perioperative therapy arm.

 XIII. To determine whether CT-based radiomics retrieved from baseline examination may act as
 non-invasive predictors of survival outcome in patients randomized to the adjuvant therapy
 arm.

 OUTLINE: Patients are randomized to 1 of 2 arms.

 ARM I: Patients receive oxaliplatin intravenously (IV) over 2 hours, irinotecan hydrochloride
 IV over 90 minutes, and leucovorin calcium over 2 hours on day 1, and fluorouracil IV over
 46-48 hours on days 1-3. Treatment repeats every 14 days for 8 cycles in the absence of
 disease progression or unacceptable toxicity. Within 2-8 weeks of completing neoadjuvant
 chemotherapy, patients undergo surgical resection. Patients then receive oxaliplatin IV over
 2 hours, irinotecan hydrochloride IV over 90 minutes, and leucovorin calcium over 2 hours on
 day 1, and fluorouracil IV over 46-48 hours on days 1-3. Treatment repeats every 14 days for
 4 cycles in the absence of disease progression or unacceptable toxicity.

 ARM II: Patients undergo surgical resection. Beginning 3-12 weeks after surgery, patients
 then receive oxaliplatin IV over 2 hours, irinotecan hydrochloride IV over 90 minutes, and
 leucovorin calcium over 2 hours on day 1, and fluorouracil IV over 46-48 hours on days 1-3.
 Treatment repeats every 14 days for 12 cycles in the absence of disease progression or
 unacceptable toxicity.

 After completion of study treatment, patients are followed up for 6 years.
Inclusion Criteria:

 PRE-REGISTRATION:

 -  Pathology: Histologic or cytologic proof of pancreatic adenocarcinoma or adenosquamous
 carcinoma

 -  TNM Stage: Tx-4, N0-1, M0 (M0 disease does not include spread to distant lymph nodes
 and organs)

 -  Resectable Primary Tumor: Local radiographic reading must be consistent with
 resectable disease defined as the following on 1) arterial and venous phase
 contrast-enhanced abdominal/pelvic CT scan or abdominal/pelvic magnetic resonance
 imaging (MRI) scan and 2) chest CT:

 -  No involvement or abutment of the celiac artery, common hepatic artery, superior
 mesenteric artery, or replaced right hepatic artery (if applicable)

 -  Less than 180 degree interface between tumor and vessel wall of the portal vein
 or superior mesenteric vein, and patent portal vein/splenic vein confluence

 -  No evidence of metastatic disease

 -  Measurable disease or non-measurable disease o Non-measurable disease is defined as
 cytologic or histologic confirmation of adenocarcinoma of adenosquamous carcinoma by
 fine needle aspiration or core-biopsy of the pancreas without measurable disease by
 radiographic imaging

 REGISTRATION:

 -  Confirmation of resectable disease by real-time central imaging review by the Alliance
 Imaging Core Lab at Imaging and Radiation Oncology Core (IROC) Ohio

 -  Determined to be appropriate candidate for curative-intent pancreatectomy by surgeon
 intending to perform the resection

 -  No prior radiation therapy, chemotherapy, targeted therapy, investigational therapy,
 or surgery for pancreatic cancer

 -  Not pregnant and not nursing, because this study involves an agent that has known
 genotoxic, mutagenic, and teratogenic effects.

 -  Therefore, for women of childbearing potential only, a negative pregnancy test done =<
 14 days prior to registration is required

 -  Eastern Cooperative Oncology Group (ECOG) performance status 0-1

 -  Total Neuropathy Score < 2

 -  Absolute neutrophil count (ANC) >= 1,500/uL

 -  Platelet count >= 100,000/uL

 -  Total bilirubin =< 1.5 x upper limit of normal (ULN) (If obstructive jaundice is
 present, then biliary drainage must be initiated and total bilirubin =< 3.0)

 -  Creatinine =< 1.5 x ULN OR calculated (Calc.) creatinine clearance >= 30 mL/min
 (Calculated using the Cockcroft-Gault equation)

 -  No known Gilbert's Syndrome or known homozygosity for UGAT1A1*28 polymorphism

 -  No comorbid conditions that would prohibit curative-intent pancreatectomy

 -  Chronic concomitant treatment with strong inhibitors of CYP3A4 is not allowed on this
 study. Patients on strong CYP3A4 inhibitors must discontinue the drug prior to
 registration

 -  Chronic concomitant treatment with strong inducers of CYP3A4 is not allowed on this
 study. Patients on strong CYP3A4 inducers must discontinue the drug prior to
 registration