Alternative Neoadjuvant Chemotherapy in Resectable and Borderline Resectable Pancreatic Cancer

Alternating Neoadjuvant Gemcitabine-Nab-Paclitaxel and Nanoliposomal Irinotecan (Nal-IRI) With 5-Fluorouracil and Folinic Acid (Leucovorin) Regimens in Resectable and Borderline Resectable Pancreatic Cancer

Using alternative neoadjuvant gemcitabine-nab-paclitaxel and nal-IRI with 5-Fluorouracil (5FU) and folinic acid (Leucovorin) regimens of localized cancer, we hope to ensure exposure of the cancer to a broader array of potentially active agents. Also, potentially improves patient tolerance and minimizes significant drug toxicity that could impair delivery of all treatment elements. Furthermore, it may enable prediction of superior to inferior treatment outcomes at an earlier point in the disease progress.

This research study is a Phase Ib clinical trial. It will assess the Safety, tolerability, and feasibility of gemcitabine-nab paclitaxel alternating with nal-IRI/5FU/leucovorin (NAPOLI) in de novo resectable and borderline resectable pancreatic cancer.

Subjects must have a newly diagnosed resectable or borderline resectable pancreatic ductal cancer and meet all inclusion/exclusion criteria.

Treatment consists of 4 week treatment cycles. Nab-paclitaxel and gemcitabine will be administered on days 1,8, and 15 with NAPOLI will be administered on days 1 and 15.

Inclusion Criteria:

1. Pathologically proven resectable or borderline resectable pancreatic cancer per current NCCN criteria (http://www.nccn.org/professionals/physician\_gls/f\_guidelines.asp).

2. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0/1.

3. Adequate bone marrow reserves as evidenced by:

   • absolute neutrophil count (ANC) ≥1,500 cells/μl without the use of hematopoietic growth factors; and
   • Platelet count ≥100,000 cells/μl; and
   • Hemoglobin ≥9 g/dL (blood transfusions are permitted for patients with hemoglobin levels below 9 g/dL).

4. Adequate hepatic function as evidenced by:

   • Serum total bilirubin within normal range for the institution (biliary drainage is allowed for biliary obstruction); and

   • aspartate aminotransferase (AST) and alanine aminotransferase (ALT)

     • 2.5 x upper limit of normal (ULN) (≤5 x ULN is acceptable if liver metastases are present).

5. Adequate renal function as evidenced by a serum creatinine ≤1.5 x ULN.

6. At least 18 years of age.

7. Women of child-bearing potential (defined as a sexually mature woman who (1) has not undergone hysterectomy [the surgical removal of the uterus] or bilateral oophorectomy [the surgical removal of both ovaries] or (2) has not been naturally postmenopausal for at least 24 consecutive months [i.e., has had menses at any time during the preceding 24 consecutive months]) must: Either commit to true abstinence from heterosexual contact (which must be reviewed on a monthly basis), or agree to use, and be able to comply with, effective contraception without interruption for 28 days prior to starting study medications (including dose interruptions) and for 3 months after last dose of study medication and Have a negative pregnancy test result at screening and agree to ongoing pregnancy testing at the Investigator's discretion during the course of the study. This applies even if the subject practices true abstinence from heterosexual contact.

8. Male subjects must practice true abstinence or agree to use a condom during sexual contact with a female of childbearing potential or a pregnant female while on treatment (including during dose interruptions) with study medications and for 3 months following the last dose of study medication, even if he has undergone a successful vasectomy.

Exclusion Criteria:

1. Prior therapy for pancreatic cancer (e.g., attempted surgery, chemotherapy, radiation therapy).
2. Any contraindication to curative surgery.
3. History of any second malignancy in the last 5 years except in-situ cancer or basal or squamous cell skin cancer. Subjects with history of other malignancies are eligible if they have been continuously disease free for at least 5 years.
4. Severe arterial thromboembolic events (myocardial infarction, unstable angina pectoris, stroke) less than 6 months before study participation.
5. New York Heart Association (NYHA) Class III or IV congestive heart failure, ventricular arrhythmias or uncontrolled blood pressure.
6. Active infection or an unexplained fever >38.5°C during screening visit or on the first scheduled day of dosing in each cycle which, in the Investigator's opinion, might compromise the subject's participation in the trial or affect the study outcome. Subjects with tumor fever may be enrolled at the discretion of the Investigator.
7. Known hypersensitivity to any of the components of nal-IRI, other liposomal products, fluoropyrimidines or leucovorin.
8. Neuropathy > grade 1.
9. Investigational therapy administered within 4 weeks, or within a time interval less than at least 5 half-lives of the investigational agent, whichever is longer, prior to the first scheduled day of dosing in this study.
10. Any other medical or social condition deemed by the Investigator to be likely to interfere with a subject's ability to sign informed consent, cooperate and/or participate in the study in any way, or interfere with the interpretation of the results.
11. Inability or unwillingness to provide written informed consent.
12. Patients who are not appropriate candidates for participation in this clinical study for any other reason as determined by the investigator.