Inclusion Criteria:

- Histologically or cytologically confirmed metastatic pancreatic adenocarcinoma

- Not amenable to potentially curative surgical resection

- At least 1 prior regimen of chemotherapy, preferably gemcitabine-based, for
metastatic disease

- Evidence of disease progression

- Measurable disease defined as ≥ 1 lesion that can be accurately measured in ≥ 1
dimension (longest diameter to be recorded) as ≥ 20 mm by conventional techniques or
as ≥ 10 mm by spiral CT scan

- Available archived tumor tissue (baseline core biopsies or surgical tumor blocks)

- No diagnosis by fine-needle aspiration only

- No known brain metastases

- ECOG performance status (PS) 0-1 (Karnofsky 70-100%)

- WBC ≥ 3,000/mm³

- ANC ≥ 1,500/mm³

- Platelet count ≥ 100,000/mm³

- Hemoglobin ≥ 9 g/dL

- Total bilirubin normal

- AST and ALT ≤ 2.5 times upper limit of normal (ULN) (5 times ULN if liver metastases
present)

- Creatinine normal OR creatinine clearance ≥ 60 mL/min

- Willingness to undergo 2 tumor biopsies, if required

- Fertile patients must use 2 forms of contraception (i.e., barrier contraception and
one other method of contraception) ≥ 4 weeks prior to, during, and for ≥ 12 months
after completion of therapy

- Negative pregnancy test

- Not pregnant or nursing

- Able to swallow pills

- No patients with malabsorption syndrome or other condition that would interfere with
intestinal absorption

- No history of allergic reactions attributed to compounds of similar chemical or
biologic composition to gamma secretase inhibitor RO4929097

- Not serologically positive for hepatitis A, B, or C

- No history of liver disease, other forms of hepatitis, or cirrhosis

- No uncontrolled hypocalcemia, hypomagnesemia, hyponatremia, hypophosphatemia, or
hypokalemia despite adequate electrolyte supplementation

- No uncontrolled intercurrent illness including, but not limited to, any of the
following:

- Ongoing or active infection

- Symptomatic congestive heart failure

- Unstable angina pectoris

- Cardiac arrhythmia other than chronic, stable atrial fibrillation

- Psychiatric illness/social situations that would limit compliance with study
requirements

- No baseline QTcF > 450 msec (male) or QTcF > 470 msec (female)

- No other malignancy within the past 5 years except curatively treated basal cell
carcinoma of the skin or carcinoma in-situ of the uterine cervix

- No combination antiretroviral therapy for HIV-positive patients

- Recovered to < NCI CTCAE grade 2 toxicities from prior therapy

- More than 3 weeks since prior chemotherapy for metastatic disease (6 weeks for
carmustine or mitomycin C)

- At least 4 weeks since prior radiotherapy

- Concurrent low-molecular weight heparin (LMWH) or full-dose coumadin allowed

- INR must be monitored as clinically indicated

- No other concurrent investigational agents

- No concurrent strong CYP3A4 inhibitors or inducers, including the following:

- Strong inhibitors: Amiodarone, erythromycin, clarithromycin, grapefruit juice,
isoniazid, ketoconazole, itraconazole, or nefazodone

- Patients taken off strong inhibitors allowed provided they have ≥ 1-week
washout period

- Strong inducers: Carbamazepine, pentobarbital, phenobarbital, phenytoin,
Rifabutin, Rifampin, or St. John wort

- Patients taken off strong inducers allowed provided they have ≥ 2-week
washout period

- No concurrent antiarrhythmics or other medications known to prolong QTc