Gamma Secretase Inhibitor RO4929097 in Previously Treated Metastatic Pancreas Cancer
Condition: Adenocarcinoma of the Pancreas; Recurrent Pancreatic Cancer; Stage IV Pancreatic Cancer
MeSH terms: Pancreatic Neoplasms
Intervention: gamma-secretase/Notch signalling pathway inhibitor RO4929097
Intervention description: Given PO
Intervention MeSH terms: 2,2-dimethyl-N-(6-oxo-6,7-dihydro-5H-dibenzo(b,d)azepin-7-yl)-N'-(2,2,3,3,3-pentafluoropropyl)malonamide
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 18.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      This phase II trial is studying how well RO4929097 (gamma-secretase/Notch signalling pathway
      inhibitor RO4929097) works in treating patients with previously treated metastatic pancreatic
      cancer. RO4929097 may stop the growth of tumor cells by blocking some enzymes needed for cell
      growth.
    

Eligibility criteria:

        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