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

PRIMARY OBJECTIVES:

I. To estimate the efficacy, as determined by progression-free survival, of FOLFOX6 and
bevacizumab with versus without gamma-secretase inhibitor RO4929097 (RO4929097).

SECONDARY OBJECTIVES:

I. To estimate the clinical benefit of RO4929097 in combination with mFOLFOX6 and
bevacizumab, as measured by objective response rate.

II. To evaluate the safety and tolerability of RO4929097 in combination with mFOLFOX6
chemotherapy and bevacizumab.

III. To evaluate the pharmacokinetics (PK) and pharmacodynamics (PD) of RO4929097 in
combination with mFOLFOX6 and bevacizumab.

IV. To investigate PD response of RO4929097 in combination with mFOLFOX6 chemotherapy and
bevacizumab, as assessed by direct measurement of gamma-secretase enzyme activity, in tumor
samples.

V. (Exploratory) To investigate the Notch signaling pathway genes targeted by RO4929097 in
combination with mFOLFOX6 chemotherapy and bevacizumab and correlate with clinical outcome.

VI. (Exploratory) To investigate the Ras signaling pathway genes targeted by RO4929097 in
combination with mFOLFOX6 chemotherapy and bevacizumab and correlate with clinical outcome.

VII. (Exploratory) To investigate putative colorectal cancer stem cells targeted by
RO4929097 in combination with mFOLFOX6 chemotherapy and bevacizumab and correlate with
clinical outcome.

OUTLINE: This is a multicenter study. Patients are stratified according to participating
center, prior therapy (adjuvant/neoadjuvant vs none), and number of organs* involved by
metastases (1 vs > 1). Patients are randomized to 1 of 2 treatment arms.

NOTE: *Lesions all in the liver would be considered as 1 organ involved.

ARM I: Patients receive FOLFOX6 regimen comprising oxaliplatin intravenously (IV) over 2
hours, leucovorin calcium IV over 2 hours, fluorouracil IV continuously over 46 hours, and
bevacizumab IV over 30-90 minutes on days 1-2. Patients also receive oral gamma-secretase
inhibitor RO4929097 on days 1-3 and 8-10.

Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity
(RO4929097 is given for up to 12 courses).

ARM II: Patients receive FOLFOX6 regimen and bevacizumab as in arm I.

Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.
Patients may undergo blood sample collection at baseline and periodically during study for
pharmacokinetic, pharmacodynamic, and correlative studies.

After completion of study therapy, patients are followed up for 12 months.

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