A Study of Administering FOLFIRINOX Before Surgery For Potentially Curable Pancreatic Cancer
A Study of Administering FOLFIRINOX Before Surgery For Potentially Curable Pancreatic Cancer
Pancreatic cancer is a serious condition and is one of the leading cause of cancer related
 health problem. It is estimated that in 2016, 5,200 Canadians will be diagnosed with
 pancreatic cancer, and approximately 20% (1 in 5) of patients will have localized cancer
 (cancer that is limited to pancreas and there is no evidence of cancer in other parts of the
 body). Localized cancer is earlier stage of disease and surgery to remove the cancer is
 standard of care in this condition. However, recent scientific and clinical studies show that
 using the chemotherapy medication before surgery can improve the overall survival in patents
 with localized pancreatic cancer. One of these chemotherapy regimen is combination of
 fluorouracil, oxaliplatin, irinotecan, leucovorin (FOLFIRINOX) that we are going to evaluate
 its effect in this study.

 Because of promising result of this combination in more advanced stage of pancreatic cancer,
 this study is going to examine its efficiency in earlier stage of pancreatic cancer
 (localized form). Total number of participant in this study will be 20 patients with
 localized form of pancreatic cancer without any evidence of cancer in other parts of the
 body.

 Laboratory tests show that it works by slowing down the growth of cancer or may cause cancer
 cells to die. It is hoped that by shrinking the tumor size, the surgeon will be able to
 remove the cancer and improve the overall survival.

 Procedures start with 2 weeks of comprehensive evaluation. Approximately 20 eligible
 subjects, based on this study criteria, will receive 6 treatment of this regimen every 2
 weeks. Once 6 treatments have been completed, comprehensive re-evaluation procedures will be
 repeated, and subjects without disease progression or unacceptable toxicity will continue on
 their treatment based on treating team decision (surgical intervention, radiation therapy or
 continue FOLFIRINOX or different regimen). Patients then will follow with CT scan, blood test
 and physical examination every 3 months.
Approximately 20% of patients present with potentially curable pancreatic cancers-resectable
 or borderline resectable tumors- for which surgical resection is an appropriate
 consideration. However, even after multimodality therapy that includes surgical resection,
 5-year OS rates only reach 25% to 30% at best.

 Surgical resection represents the standard of care for patients with early-stage pancreatic
 cancer. However, while surgical morbidity and mortality have improved over the past few
 decades, overall survival for pancreatic cancer has remained low. Given the increasing
 survival rates associated with modern chemotherapy regimens, the risks of surgery, the
 likelihood of R0 resection, the likelihood of subclinical metastatic disease, and the
 likelihood of receiving postoperative therapy (50% of patients receive post-operative
 chemotherapy) are our logic to evaluate preoperative chemotherapy as an alternative treatment
 strategy for these patients.

 The main advantage of neoadjuvant chemotherapy in treating pancreatic cancer is that it
 significantly increases the likelihood of receiving both surgery and chemotherapy. (Winner et
 al., Seminars in Oncology, 2015). It is well accepted that the best results are achieved when
 both modalities are used. Recently, the use of FOLFIRINOX has emerged as an alternative in
 pancreatic cancer. A randomized trial of FOLFIRINOX versus gemcitabine in metastatic
 pancreatic cancer showed improved median survival from 6.8 to 11.1 months.

 According to ACCORD-11 trial,FOLFIRINOX in advanced metastatic disease have demonstrated
 improved response rates compared with gemcitabine and other historical treatments while
 maintaining or improving quality of life with the median overall survival was 11.1 months
 FOLFIRINOX group as compared with 6.8 months in the gemcitabine group. Median
 progression-free survival was 6.4 months in the study regimen group and 3.3 months in the
 gemcitabine group, and at 6 months, 31% of the patients FOLFIRINOX group had a definitive
 degradation of the quality of life versus 66% in the gemcitabine group.

 The role of preoperative therapy for patients with potentially curable pancreatic cancer is
 still unclear. The ongoing study (adjuvant gemcitabine versus neoadjuvant
 gemcitabine/oxaliplatin plus adjuvant gemcitabine in resectable pancreatic cancer) is a
 prospective randomized clinical trial that is anticipated to clarify the role of preoperative
 chemotherapy. However, this ongoing clinical trial does not use contemporary chemotherapy
 regimens with proven efficacy in higher stage settings such as FOLFIRINOX. There are only few
 studies evaluate this regimen in this setting.The encouraging results reported from ACCORD-11
 and consequent clinical investigations prompted our group to evaluate our experience with
 FOLFIRINOX regimen in a selected population composed of patients with potentially curable
 pancreatic cancer (resectable and borderline resectable).

 In this clinical trial, our primary objective is to evaluate and estimate Time to Progression
 (TTP). However, our secondary objectives are to determine Overall Response Rate (ORR), R0 and
 R1 Resection Rate, assessment of safety and toxicity associated with study regimen, and
 finally, to investigate Overall survival (OS).

 Pre-treatment procedures start with 2 weeks of comprehensive staging evaluation.
 Approximately 20 eligible subjects, based on inclusion/exclusion criteria will receive study
 regimen for 6 treatment every 2 weeks. Once 6 treatments have been completed, comprehensive
 re-staging procedures will be repeated, and subjects without disease progression or
 unacceptable toxicity will continue on their treatment contingent upon treating team decision
 (surgical intervention, radiation therapy or continue chemotherapy with FOLFIRINOX or
 different regimen). Patients then follow with CT scan, cancer antigen 19-9 and physical
 examination every 3 months.

 Subjects will be considered active study participants from enrollment up to survival
 follow-up period until documented disease progression, withdrawal of consent, lost to
 follow-up, or death (by any cause), whichever is earliest.
Inclusion Criteria:

 -  Subjects must satisfy the following criteria to be enrolled in the study:

 1. ≥ 18 years of age at the time of signing the informed consent form.

 2. Understand and voluntarily sign an informed consent document prior to any study
 related assessments/procedures conducted.

 3. Histologically or cytologically confirmed adenocarcinoma of the pancreas.

 4. Performance status or Comorbidity condition not currently appropriate (but
 potentially reversible) for a major abdominal operation.

 Acceptable hematology parameters:

 1. Absolute neutrophil count (ANC) ≥ 1500 cell/mm3

 2. Platelet count ≥ 100,000/mm3 without transfusion support.

 3. Hemoglobin (Hgb) ≥ 9 g/dL

 Acceptable blood chemistry levels:

 1. Hepatic transaminases (ALT and AST) less than 2.5× the upper limits of
 normal (ULN)

 2. Total bilirubin level less than 1.5 × the upper limits of normal (ULN) or in
 patient with Biliary stenting less than 2 mg/dL

 3. Serum creatinine level less than 1.5 × the upper limits of normal (ULN) or
 creatinine clearance (Ccr) ≥ 40 mL/min.

 4. Alkaline phosphatase ≤ 2.5 x ULN

 5. Serum albumin > 3 g/dL

 Absence of poorly controlled comorbid conditions:

 1. Congestive heart failure (CHF)

 2. Chronic obstructive pulmonary disease (COPD)

 3. Uncontrolled diabetes mellitus (DM)

 4. Neurologic disorders (not acutely related to pancreatic cancer) or limit
 function

 5. Radio-graphically suspicious but not diagnostic for extra-pancreatic disease,

 1. Superior mesenteric vein and portal vein confluence that can be
 reconstructed even if short segment venous occlusion is present (i.e. a
 suitable portal vein above, and a suitable Superior mesenteric vein below
 the area of occlusion);

 2. Tumor abutment of the Superior mesenteric artery of ≤180⁰,

 3. Short segment encasement of the hepatic artery amenable to resection and
 reconstruction (this is usually at the origin of the gastroduodenal artery
 and reconstruction may or may not require interposition grafting with a
 short segment of reversed saphenous vein).

 6. Cancer antigen 19-9 level (in absence of jaundice) ≥ 100u/ml suggestive of
 disseminated disease.

 7. Preoperative treatment is recommended as an alternative for patients with
 potentially curable pancreatic cancer who meet all of the following criteria:

 no clinical evidence for metastatic disease, a performance status and comorbidity condition
 appropriate for a major abdominal operation, no radiographic interface between primary
 tumor and mesenteric vasculature on imaging, an acceptable Cancer antigen 19-9 level.

 Exclusion Criteria:

 -  The presence of any of the following will exclude a subject from enrollment:

 1. Pancreatic tumors of endocrine or mixed origin.

 2. Prior anticancer therapy for pancreatic carcinoma.

 3. Presence of or history of metastatic pancreatic adenocarcinoma.

 4. Any other malignancy within 5 years prior to enrollment, with the exception of
 adequately treated in-situ carcinoma of the prostate (Gleason score ≤ 7), cervix,
 uteri, or non-melanomatous skin cancer (all treatment of which should have been
 completed 6 months prior to enrollment).

 5. Active bacterial, viral, or fungal infection(s) requiring systemic therapy,
 defined as ongoing signs/symptoms related to the infection without improvement
 despite appropriate antibiotics, antiviral therapy, and/or other treatment.

 6. Known infection with hepatitis B or C, or history of human immunodeficiency virus
 (HIV) infection, or subject receiving immunosuppressive or myelo-suppressive
 medications that would, in the opinion of the Investigator, increase the risk of
 serious neutropenic complications.

 7. History of allergy or hypersensitivity to study regimen or any of their
 excipients.

 8. Peripheral sensory neuropathy Grade > 1.

 9. Clinically significant ascites.

 10. Plastic biliary stent. (Metal biliary stent is allowed.)

 11. Serious medical risk factors involving any of the major organ systems, or serious
 psychiatric disorders, which could compromise the subject's safety or the
 integrity of the study data. These include, but are not limited to:

 1. History of connective tissue disorders (e.g., lupus, scleroderma, arteritis
 nodosa)

 2. History of interstitial lung disease, slowly progressive dyspnea and
 unproductive cough, sarcoidosis, silicosis, idiopathic pulmonary fibrosis,
 pulmonary hypersensitivity pneumonitis, or multiple allergies

 3. History of the following within 6 months prior to treatment 1 Day 1: a
 myocardial infarction, severe/unstable angina pectoris, coronary/peripheral
 artery bypass graft, New York Heart Association (NYHA) Class III-IV heart
 failure, uncontrolled hypertension, clinically significant cardiac
 dysrhythmia or electrocardiogram (ECG) abnormality, cerebrovascular
 accident, transient ischemic attack, or seizure disorder

 12. Enrollment in any other clinical protocol or investigational study with an
 interventional agent or assessments that may interfere with study procedures.

 13. Any significant medical condition, laboratory abnormality, or psychiatric illness
 that would prevent the subject from participating in the study.

 14. Any condition including the presence of laboratory abnormalities, which places
 the subject at unacceptable risk if he/she were to participate in the study.

 15. Any condition that confounds the ability to interpret data from the study.

 16. Unwillingness or inability to comply with study procedures.

 17. Pregnant or breast feeding.