Tumor Subtypes in Subjects on FOLFIRINOX With Non-Metastatic Pancreatic Cancer

This is a research study to evaluate how the genetic makeup of Pancreatic Ductal Adenocarcinoma (PDAC) can affect the response to FDA-approved chemotherapy treatment, FOLFIRINOX, given before surgery to remove the tumor. Certain types of PDAC tumors can be surgically resected (removed). However, not all types of PDACs are resectable, especially if they are close to important structures like blood vessels or intestines. These types of PDACs are treated with chemotherapy such as FOLFIRINOX. Research studies showed that chemotherapy after surgical resection of PDAC tumors reduced the risk of the cancer returning.

Chemotherapy is used to treat PDAC that has not spread outside of the pancreas and is not resectable. FOLFIRINOX is a chemotherapy treatment that combines multiple chemotherapeutic agents, including oxaliplatin, leucovorin, irinotecan, and 5-FU. Patients receive these agents by intravenous infusion. Of these drugs, 5-FU requires you to return home with a chemotherapy pump that will deliver chemotherapy over 46 hours. This regimen has been studied in pancreatic cancer that has been removed with surgery as a method for preventing the cancer from returning. Studies showed FOLFIRINOX chemotherapy reduced the risk of cancer returning and increased patients survival. In this study, researchers want to know if FOLFIRINOX chemotherapy given before surgery will make the cancer easier to remove with surgery and increase the chances of the cancer staying away after surgery.

Researchers have shown that pancreatic cancers are not all the same when you look at the DNA and RNA that is inside a pancreatic cancer cell.

Depending on the expression of different genes in a cancer cell, some pancreatic cancers may respond differently to chemotherapy. In this study researchers want to know if FOLFIRINOX chemotherapy can change the genetic profile of the cancer. This will be studied by obtaining a biopsy of the cancer before the start of chemotherapy, and after 8 treatments of chemotherapy. They will also study cancer cells that will be collected from blood samples.

This is a single arm, phase II clinical trial designed to assess the impact of tumor and stromal molecular subtypes on the efficacy of neoadjuvant FOLFIRNOX in untreated subjects with resectable, borderline resectable and unresectable locally advanced pancreatic ductal adenocarcinoma (PDAC). Subjects will undergo an EUS-guided core biopsy of the pancreas prior to treatment and after cycle 8 of FOLFIRINOX. Imaging will be performed after every 4 cycles of chemotherapy (8 weeks) and reassessed for resectability after 12 cycles. If patients show a response to treatment that is deemed by the surgical oncologist to be amenable to resection, surgery can be pursued after 8 cycles of therapy. In this case, the remaining 4 cycles of treatment will be given after surgery.

Duration of Therapy:

In the absence of treatment delays due to adverse events, treatment may continue until:

* Disease progression,
* Inter-current illness that prevents further administration of treatment,
* Unacceptable adverse event(s),
* Subject decides to withdraw from the study, or
* General or specific changes in the subject's condition render the subject unacceptable for further treatment in the judgment of the investigator.

Duration of Follow Up:

- Subjects will be followed for 36 months after removal from study treatment or until death, whichever occurs first. Subjects removed from study treatment for unacceptable adverse events will be followed until resolution or stabilization of the adverse event.

Eligibility Criteria:
Inclusion Criteria:

* Written informed consent obtained to participate in the study and HIPAA authorization for release of personal health information.
* Histologically or cytologically confirmed adenocarcinoma of the pancreas with no evidence of distant metastatic disease.
* Subject has no evidence of co-morbidities precluding the potential to undergo surgical resection of PDAC as determined by surgical investigator.
* Subjects must be willing to undergo a mandatory pre- and post-treatment EUS guided core biopsy of the pancreatic mass.
* Measurable or non-measurable but evaluable (as determined by Response Evaluation Criteria in Solid Tumors version 1.1 \[RECIST 1.1\]) resectable, borderline resectable or unresectable locally advanced PDAC.
* Subject has adequate performance status as defined by ECOG performance status 0 or 1.
* Subject has received no prior chemotherapy or chemoradiotherapy for pancreatic cancer. Subjects have not previously received surgery to remove pancreatic cancer.
* Age ≥ 18 years of age.
* Subject has adequate organ function at study entry, as demonstrated by:

  * Hemoglobin ≥ 9 g/dL
  * ANC ≥ 1.5 × 109/L
  * Platelets ≥ 100 × 109/L
  * Creatinine ≤ 1.5 × ULN, or creatinine clearance ≥ 50 mL/min (as measured according to Cockcroft-Gault equation)
  * Total bilirubin ≤ 1.5 × ULN
  * AST/ALT ≤ 3 × ULN
  * GGT ≤ 5 × ULN.
* Subject has life expectancy of at least 6 months.
* Female subjects of childbearing potential must have a negative serum or urine pregnancy test performed within 14 days prior to initiation of FOLFIRINOX.
* Female subjects of childbearing potential and male subjects must agree to use adequate contraception prior to study entry, for the duration of study participation, and 8 weeks after the end of treatment.

Exclusion Criteria:

* Subject has any evidence of local recurrence or metastatic pancreatic cancer.
* Other malignancies within the past 5 years except for adequately treated cervical or vulvar carcinoma in situ, treated basal cell carcinoma, superficial bladder tumors (Ta, Tis and T1).
* Subject has hypersensitivity to 5FU, oxaliplatin or other platinum agent, or irinotecan or to their excipients.
* Subject has known dihydropyrimidine dehydrogenase (DPD) enzyme deficiency.
* Participation in any investigational drug study within 4 weeks preceding the start of study treatment. Subjects are not permitted to participate in another investigational drug study while being treated on this protocol.
* Subject has current evidence of any condition that makes participating in this study not in the best interest of the subject, including but not limited to:

  * Myocardial infarction within the past 6 months
  * New York Heart Association (NYHA) Class III or IV heart disease
  * Active infection requiring IV antibiotics
* Subject has a history of or suspected Gilbert's syndrome or known homozygosity for UGT1A1\*28 polymorphism (baseline testing not required).
* Subject has sensory peripheral neuropathy grade ≥ 2.
* Major surgery, open biopsy or significant traumatic injury within 4 weeks of first study drug.
* Subject is unable or unwilling to discontinue use of ketoconazole or St John's wort. Use of phenytoin, carbamazepine, phenobarbital, rifampin and rifabutin is discouraged, but not contraindicated. If subjects require phenytoin, carbamazepine or phenobarbital monitoring of drug levels is suggested during the study.
* Subject is pregnant or lactating.
* Psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the subject before registration in the trial.