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