Inclusion Criteria:

- Histologically or cytologically confirmed adenocarcinoma of the colon or
adenocarcinoma of the rectum

- Metastatic disease by imaging

- Measurable disease, defined as ≥ 1 lesion that can be accurately measured in ≥ 1
dimension (longest diameter to be recorded) as ≥ 20mm by conventional techniques or
as ≥ 10 mm by spiral CT scan

- No known brain metastases

- ECOG performance status 0-1

- ANC ≥ 1,500/mm³

- WBC ≥ 3,000/mm³

- Platelet count ≥ 100,000/mm³ (without a platelet transfusion ≤ 14 days prior to
study)

- Hemoglobin ≥ 9 g/dL

- Serum creatinine ≤ 1.5 times upper limit of normal (ULN)

- Urine protein:creatinine ≤ 0.5 or proteinuria < 1,000 mg on 24-hour urine collection

- Total bilirubin ≤ 1.5 times ULN

- AST and ALT ≤ 2.5 times ULN (≤ 5.0 times ULN for patients with liver metastases)

- Albumin ≥ 2.5 g/dL

- Amylase ≤ 2 times ULN

- Lipase ≤ 2 times ULN

- PTT ≤ 1.2 times ULN

- INR ≤ 1.2 times ULN

- No patients with uncontrolled hypophosphatemia, hypocalcemia, hypomagnesemia,
hyponatremia, or hypokalemia defined as less than the lower limit of normal for the
institution, despite adequateelectrolyte supplementation

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use two forms of contraception (i.e., barrier contraception and
one other method of contraception) prior to, during, and for ≥ 12 months after study
participation

- Patients must not have current evidence of or history of another malignancy except
adequately treated non-melanoma skin cancer, curatively treated in-situ cancer of the
cervix, or other curatively treated solid tumors with no evidence of disease for ≥ 3
years prior to enrollment

- Able to swallow capsules

- No 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 used in the study

- No clinically important history of liver disease, including known viral, other
hepatitis, or cirrhosis

- No uncontrolled intercurrent illness including, but not limited to, any of the
following:

- Ongoing or active infection

- Symptomatic congestive heart failure

- Unstable angina pectoris

- A history of torsades de pointes or other significant cardiac arrhythmias

- Psychiatric illness and/or social situations that would limit compliance with
study requirements

- No baseline QTcF > 450 msec (male) or QTcF > 470msec (female)

- No serious or non-healing wound, ulcer, or bone fracture

- No history of abdominal fistula, gastrointestinal perforation, or intra-abdominal
abscess within the past 6 months

- No significant traumatic injury within the past 28 days

- No clinically significant cardiovascular disease, including any of the following:

- Inadequately controlled hypertension (systolic BP > 160 mm Hg and/or diastolic
BP > 90 mm Hg despite antihypertension medication)

- History of cerebrovascular accident within the past 6 months

- Myocardial infarction or unstable angina within the past 6 months

- NYHA grade II-IV congestive heart failure

- Serious and inadequately controlled cardiac arrhythmia

- No requirement for antiarrhythmics or other medications known to prolong QTc

- No significant vascular disease (e.g., aortic aneurysm, requiring surgical repair,
history of aortic dissection, or recent peripheral arterial thrombosis) within the
past 6 months

- No clinically significant peripheral vascular disease

- No evidence of bleeding diathesis or coagulopathy

- No known hypersensitivity to Chinese hamster ovary cell products or other recombinant
human antibodies

- Recovered to < NCI CTCAE grade 2 toxicities related to prior therapy

- No prior adjuvant or neoadjuvant chemotherapy for colorectal cancers within 12 months
of development of metastases

- No prior chemotherapy or gamma-secretase inhibitors or other investigational agents
for metastatic colorectal cancer

- No prior radiotherapy for colorectal cancers including in the neoadjuvant or adjuvant
setting within 12 months of development of metastases

- No major surgical procedure or open biopsy within the past 28 days and no
anticipation of need for major surgical procedures during the course of the study

- No concurrent medications with narrow therapeutic indices that are metabolized by
cytochrome P450 (CYP450), including warfarin sodium (Coumadin®)

- Patients who switch from warfarin sodium to alternative anti-coagulant agents
allowed

- No concurrent medications that are strong inducers, inhibitors, or substrates of
CYP3A4, including ketoconazole and grapefruit juice

- No concurrent combination antiretroviral therapy for HIV-positive patients