Gamma Secretase Inhibitor RO4929097 in Previously Treated Metastatic Pancreas Cancer

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