Neoadjuvant CAPOXIRI Chemotherapy in the Treatment of Pancreatic Adenocarcinoma Protocol

Introduction:

This is a phase II study evaluating the treatment adherence rate, efficacy and safety of
neoadjuvant chemotherapy with capecitabine, oxaliplatin and irinotecan (CAPOXIRI) in patients
with resectable (able to be cut out), borderline resectable and locally advanced pancreatic
adenocarcinoma. Neoadjuvant CAPOXIRI chemotherapy is an innovative strategy that builds on
the advancement associated with oxaliplatin, irinotecan, fluorouracil, and folinate
(FOLFIRINOX regimen) chemotherapy in patients with metastatic disease. Building on the
FOLFIRINOX regimen the use of CAPOXIRI is among the most clinically relevant projects for
patients diagnosed with earlier stage pancreatic adenocarcinoma with the goal of improving
patient outcomes and advancing our knowledge and understanding of this devastating disease.

The primary end point is the treatment adherence rate (TAR) which is the percentage of
patients who complete 75% of the planned treatment (dose) for their diagnostic strata
(resectable disease and borderline resectable/locally advanced disease).

Secondary end points are: Overall survival (OS), Disease-free survival (DFS; for those
patients who are rendered disease-free by surgical resection), Progression Free Survival
(PFS), Response Rate (RR), toxicity, and R0 resection rate (for patients stratified as having
resectable disease and borderline resectable disease).

Background and Study Rationale:

It is estimated that 36,800 people will die of pancreatic cancer in the United States in
2010. Surgical resection offers the only chance of cure, but only 15-20% of cases are
potentially resectable at present. Furthermore, prognosis is poor, even for those undergoing
complete resection. Reported five-year survival rates following pancreatic-duodenectomy
(surgery of the small intestine and pancreas) for node-negative disease is 25-30% and for
node-positive disease is 10%.

The purpose of this study is to evaluate the effects of the combination of capecitabine,
oxaliplatin, and irinotecan (CAPOXIRI) on the disease. This research is being done because we
think that this combination, CAPOXIRI, may be better than other combinations used to treat
your stage of pancreatic cancer.

A research study like this one has been done which shows that a similar combination of drugs
including oxaliplatin, irinotecan and 5-fluorouracil (which is in the same class as
capecitabine) can be effective in treating patients with pancreatic cancer who have more
advanced disease than you. All of the drugs that are being used in this study have been
approved by the FDA (Food and Drug Administration).

Inclusion Criteria:

1. Histologically or cytologically confirmed diagnosis of pancreatic adenocarcinoma that
is clinically staged as resectable, borderline resectable, or locally advanced as
determined by CT criteria.

2. Age ≥ 18 years old.

3. An Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2 (Appendix B).

4. Patients must give written informed consent as per institutional and federal
regulatory requirements.

5. An interval between initial diagnosis and consent of ≤ 42 days.

6. An interval between consent and initiating protocol-directed therapy of ≤ 14 days.

7. CT scan to stratify as resectable versus borderline resectable/locally advanced status
within 28 days of initiating protocol-directed therapy.

8. A general level of health that would indicate a life expectancy of 5 years, excluding
the patient's cancer diagnosis.

9. No prior chemotherapy, immunotherapy or radiotherapy for pancreatic adenocarcinoma.

10. Patients must have measurable or evaluable disease by Response Evaluation Criteria in
Solid Tumors (RECIST) criteria (Appendix C).

11. Absolute granulocyte count of ≥ 1,500/mm3 and a platelet count of ≥ 100,000/mm3.

12. Patients must have adequate liver and renal function defined by a bilirubin of ≤ 2.0
mg/dL (with or without biliary stenting) and a creatinine of ≤ 1.5 mg/dL respectively.

13. Men and women who are fertile must use adequate contraception. Premenopausal women
must have a negative pregnancy test documented prior to study entry.

14. There must be no extra-pancreatic spread of disease.

15. Patients must not have other serious illness or medical conditions including, but not
limited to the following: New York Heart Association (NYHA) Class II or greater
congestive heart failure or unstable angina pectoris, uncontrolled hypertension or
arrhythmias, active bacterial infections, or unstable diabetes mellitus.

16. Patients must be disease-free of prior invasive malignancies for ≥ 5 years with the
exception of curatively-treated basal cell or squamous cell carcinoma of the skin.

Exclusion Criteria:

1. Patients less than 18 years of age.

2. CT evidence of metastatic disease.

3. Pregnancy or considering pregnancy at the time of study entry.

4. Breast feeding at the time of study entry.

5. Prior therapy for pancreatic cancer including irradiation, chemotherapy, or
immunotherapy.

6. Receiving concurrent chemotherapy, immunotherapy, or radiotherapy that is not part of
this protocol while participating in this study.

7. Receiving concurrent treatment with any other investigational drug while on this
protocol.

8. Prior malignancy within 5 years, excluding squamous or basal cell carcinoma of the
skin that has been effectively treated, carcinoma in situ of the cervix, lobular
carcinoma in situ of the breast, or ductal carcinoma in situ of the breast.

9. Non-malignant disease that would preclude protocol participation or follow-up.

10. Myocardial infarction within 6 months before enrollment, New York Heart Association
(NYHA) Class II or greater heart failure, uncontrolled angina, severe uncontrolled
ventricular arrhythmias, clinically significant pericardial disease, or
electrocardiographic evidence of acute ischemic or active conduction system
abnormalities.

11. Psychiatric disorders or conditions, that in the opinion of the investigator, would
preclude the patient from providing truly informed consent.

12. Presence of progressive sensory neuropathy or progressive hearing loss or tinnitus.