Intervention: RO4929097
Trial phase: Phase 2
SMILES: CC(C)(C(=O)NCC(F)(F)C(F)(F)F)C(=O)NC1C(=O)Nc2ccccc2-c2ccccc21
Sex: All
Age groups: Adult | Older Adult
Healthy volunteers: No
Participants at risk: 18
Group description: RO4929097 was administered at a dose of 20 mg daily on days 1-3, 8-10 and 15-17 of 21-day cycles.
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