Dose Escalation Trial of AZD1775 and Gemcitabine (+Radiation) for Unresectable Adenocarcinoma of the Pancreas

Inclusion Criteria:

- Patients must have pathologically confirmed adenocarcinoma of the pancreas.

- Patients will have unresectable disease, defined radiographically as >180 degrees
involvement of the superior mesenteric artery or celiac trunk or SMV/portal vein
impingement that cannot be surgically reconstructed, in the absence of distant
metastasis..

- Patients must have a Zubrod performance status (measure of general well being that
ranges from 0 to 5 where 0 represents perfect health) of < 2.

- Patients must have adequate organ function defined as follows: absolute neutrophil
count of ≥ 1500/mm3, platelets ≥ 100,000/mm3, serum creatinine ≤ 2 mg/dl, total
bilirubin ≤ 3, (with relief of biliary obstruction if present (PTC tube or endobiliary
stent)) and AST < 5 times the upper limit of normal.

- Patients of reproductive potential must agree to use an effective contraceptive method
during participation in this trial and for 6 months after the trial. Patients must not
be breastfeeding.

- Patients must be aware of the investigational nature of the therapy and provide
written informed consent.

- Patients must be at least 18 years old.

Exclusion Criteria:

- Other serious uncontrolled concomitant systemic disorders or psychiatric condition
that would interfere with the safe delivery of protocol therapy.

- A history of previous chemotherapy for pancreatic cancer or abdominal radiation
therapy.

- The use of any investigational agent in the month before enrollment into the study.

- Inability to discontinue a prescription or non-prescription drugs or other products
known to be metabolized by CYP3A4, or to inhibit or induce CYP3A4 prior to Day 1 of
dosing and to withhold throughout the study until 2 weeks after the last dose of study
medication. Medications of particular concern are the following inhibitors of CYP3A4:
azole antifungals (ketoconazole itraconazole, fluconazole and voriconazole), macrolide
antibiotics (erythromycin, clarithromycin), cimetidine, aprepitant, HIV protease
inhibitors, nefazodone and the following inducers of CYP3A4: phenytoin, barbiturates
and rifampicin. Substrates of CYP3A4 include statins (lovastatin, simvastatin),
midazolam, terfenadine, astemizole, and cisapride.