RO4929097 in Treating Patients With Previously Treated Metastatic Pancreatic Cancer

OBJECTIVES:

Primary

- To determine the 6-month survival of patients with previously treated metastatic
pancreatic cancer treated with gamma secretase RO4929097 (RO4929097).

- To determine the adverse events of RO4929097 in this patient population.

- To correlate changes in tumor markers with RO4929097 exposure.

Secondary

- To evaluate the response rate and overall survival of this population treated with
RO4929097.

- To correlate clinical outcome with tumor markers (including stem cell markers) obtained
from pre- and post- treatment biopsies. (exploratory)

- To assess variants in genes involved in RO4929097 disposition and their relation to
RO4929097 exposure.

OUTLINE: This is a multicenter study.

Patients receive oral gamma secretase inhibitor RO4929097 once daily on days 1-3, 8-10, and
15-17. Courses repeat every 21 days for up to 24 months in the absence of disease
progression or unacceptable toxicity.

Patients may undergo tumor biopsy at baseline and on days 16 or 17 of course one for
biomarker and other correlative studies. Blood samples may also collected at baseline and
periodically during study for pharmacokinetic and angiogenesis marker studies.

After completion of study therapy, patients are followed up periodically for 2 years.

DISEASE CHARACTERISTICS:

- 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

PATIENT CHARACTERISTICS:

- 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

PRIOR CONCURRENT THERAPY:

- See Disease Characteristics

- 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

- No combination antiretroviral therapy for HIV-positive patients