Gamma Secretase Inhibitor RO4929097 in Previously Treated Metastatic Pancreas Cancer

PRIMARY OBJECTIVES:

I. To determine the 6-month survival of patients with previously treated metastatic pancreas cancer treated with gamma secretase RO4929097.

II. To determine the adverse events of RO4929097 in this patient population. III. To correlate changes in tumor markers with RO4929097 exposure.

SECONDARY OBJECTIVES:

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

II. To correlate clinical outcome with tumor markers (including stem cell markers) obtained from pre- and post- treatment biopsies. (exploratory) III. To assess variants in genes involved in RO4929097 disposition and their relation to RO4929097 exposure.

OUTLINE: This is a multicenter study.

Patients receive gamma-secretase/Notch signalling pathway inhibitor RO4929097 orally (PO) 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.

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
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1 (Karnofsky 70-100%)
• White blood cell count (WBC) ≥ 3,000/mm³
• Absolute neutrophil count (ANC) ≥ 1,500/mm³
• Platelet count ≥ 100,000/mm³
• Hemoglobin ≥ 9 g/dL
• Total bilirubin normal
• Aspartate aminotransferase (AST) and Alanine Aminotransferase (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 < Common Toxicity Criteria for Adverse Effects (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

• International normalized ratio (INR) must be monitored as clinically indicated
• No other concurrent investigational agents
• No concurrent strong cytochrome P450 3A4 (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