Combination Chemotherapy and Bevacizumab With or Without RO4929097 in Treating Patients With Metastatic Colorectal Cancer

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