Ibrutinib Combined With Gemcitabine and Nab-Paclitaxel in Patients With Metastatic Pancreatic Cancer

Pancreatic adenocarcinoma (PDAC) represents the fourth leading cause of cancer-related
mortality in the United States, with an estimated 39,950 deaths attributable to PDAC in 2014
(http://seer.cancer.gov/statfacts/html/pancreas.html). Over 90% of patients have inoperable
disease at presentation, at which point systemic therapy becomes the primary form of
treatment.

Treating PDAC has been challenging and few approved drugs are available. Recently, however,
some breakthroughs have occurred, raising hope that this aggressive disease can be better
controlled. FOLFIRINOX, a combination of 5FU, oxaliplatin, and irinotecan, has been found to
be substantially superior to treatment of gemcitabine alone in patients with metastatic
disease and good performance status. Similarly, gemcitabine and nab-paclitaxel, a regimen
with less non-hematologic toxicity, demonstrated improved overall survival and
progression-free survival compared to gemcitabine alone. Both of these combinations or
modifications of these combinations are now front line options for patients with good
performance status. Furthermore, these improvements in survival, however incremental, now
afford patients with pancreatic cancer time to participate in and possibly benefit from
clinical trials of novel therapeutics.

Inclusion Criteria:

- Histologically or cytologically confirmed metastatic pancreatic adenocarcinoma

- Stage IV disease (measurable disease NOT required)

- Intact primary tumor

- CA 19-9 greater than 75 units

- ECOG performance score of 0-1

- At least 18 years of age

- Female patients who are not of child-bearing potential, and fertile female patients of
child-bearing potential, who agree to use adequate contraceptive measures, who are not
breastfeeding, and who have a negative serum or urine pregnancy test within 72 hours
prior to start of randomization.

- Fertile male patients willing to use adequate contraceptive measures.

- Adequate bone marrow function:

- Absolute neutrophil count (ANC) ≥ 1500/uL

- platelet count ≥ 100,000/uL

- hemoglobin ≥ 9.0 g/dL

- Adequate hepatic function:

- Total bilirubin ≤ 1.5 X ULN (unless bilirubin rise due to Gilbert's syndrome)

- Aspartate amino transferase (AST) (SGOT) ≤ 3.0 X ULN; ≤5.0X ULN if liver metastases
are present.

- Alanine aminotransferase (ALT) (SGPT) ≤ 3.0 X ULN; ≤0 5.0X ULN if liver metastases are
present.

- Adequate renal function (defined as serum creatinine ≤ 1.5 X ULN)

- Ability to understand the nature of this study protocol, comply with study and/or
follow-up procedures, and give written informed consent

- Willingness and ability to comply with scheduled visits, treatment plans, laboratory
tests, and other study procedures.

Exclusion Criteria:

- Any prior systemic or investigational therapy for metastatic pancreatic cancer.
Systemic therapy administered alone or in combination with radiation in the adjuvant
or neoadjuvant setting is permissible as long as it was completed > 6 months prior to
the time of study registration.

- History of other diseases, metabolic dysfunction, physical examination findings, or
clinical laboratory findings giving reasonable suspicion of a disease or condition
that, in the opinion of the investigator, renders the subject at high risk from
treatment complications or might affect the interpretation of the results of the
study.

- History of previous malignancy (except basal cell) within 5 years.

- Life expectancy of <3 months.

- Inability to undergo two sequential EUS-directed core biopsies of the primary tumor.

- Presence of known central nervous system or brain metastases.

- Known human immunodeficiency virus (HIV) infection.

- History of stroke or intracranial hemorrhage within 6 months prior to enrollment.

- Known bleeding disorders (e.g., von Willebrand's disease or hemophilia).

- Patients receiving warfarin or other Vitamin K antagonists. However, if therapeutic
anticoagulation is necessary, LMWH is the anticoagulant of choice.

- Currently active, clinically significant cardiovascular disease, such as uncontrolled
arrhythmia or Class 3 or 4 congestive heart failure as defined by the New York Heart
Association Functional Classification; or a history of myocardial infarction, unstable
angina, or acute coronary syndrome within 6 months prior to randomization.

- Current peripheral sensory neuropathy > Grade 1

- Major surgery within 4 weeks of the start of study treatment (defined as those
surgeries that require general anesthesia. Insertion of a vascular access device is
NOT considered major surgery.

- Requires treatment with a strong cytochrome P450 (CYP) 3A inhibitor.

- Unable to swallow capsules or has malabsorption syndrome, disease significantly
affecting gastrointestinal function or resection of the stomach or small bowel,
symptomatic inflammatory bowel disease or ulcerative colitis, or partial or complete
bowel obstruction.