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A Phase II Study of the Gamma Secretase Inhibitor RO4929097 in Previously Treated Metastatic Pancreas Cancer

Phase 2
18 Years
Open (Enrolling)
Adenocarcinoma of the Pancreas, Recurrent Pancreatic Cancer, Stage IV Pancreatic Cancer

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Trial Information

A Phase II Study of the Gamma Secretase Inhibitor RO4929097 in Previously Treated Metastatic Pancreas Cancer


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.


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

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

- ECOG performance status (PS) 0-1 (Karnofsky 70-100%)

- WBC ≥ 3,000/mm³

- ANC ≥ 1,500/mm³

- Platelet count ≥ 100,000/mm³

- Hemoglobin ≥ 9 g/dL

- Total bilirubin normal

- AST and ALT ≤ 2.5 times upper limit of normal (ULN) (5 times ULN if liver metastases

- 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

- 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

- 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 < 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

- INR must be monitored as clinically indicated

- No other concurrent investigational agents

- No concurrent strong 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

Type of Study:


Study Design:

Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Survival rate

Outcome Description:

The proportion of successes will be estimated by the number of successes divided by the total number of evaluable patients. If patients are lost to follow-up prior to the time required for the applicable primary endpoint, the final point estimate of the primary endpoint will be reported via the method of Kaplan and Meier (1958) which accounts for the censoring of such data at the date of last contact (last known alive). Otherwise, ninety percent confidence intervals for the true success proportion will be calculated according to the approach of Duffy and Santner (Duffy and Santer, 1987).

Outcome Time Frame:

6 months

Safety Issue:


Principal Investigator

Wells Messersmith

Investigator Role:

Principal Investigator

Investigator Affiliation:

University of Colorado Cancer Center - Anschutz Cancer Pavilion


United States: Food and Drug Administration

Study ID:




Start Date:

October 2010

Completion Date:

Related Keywords:

  • Adenocarcinoma of the Pancreas
  • Recurrent Pancreatic Cancer
  • Stage IV Pancreatic Cancer
  • Adenocarcinoma
  • Adenocarcinoma, Mucinous
  • Pancreatic Neoplasms



Johns Hopkins UniversityBaltimore, Maryland  21205
University of ColoradoDenver, Colorado  80217
University of Colorado Cancer Center - Anschutz Cancer PavilionAurora, Colorado  80045