A Phase I/II Study of RAD001, FOLFOX and Bevacizumab in Treatment of Colorectal Carcinoma

Inclusion Criteria:

- Patients with advanced or metastatic colorectal cancers for whom chemotherapy is
indicated

- Patients must not have had prior chemotherapy for advanced or metastatic disease.
Patients could have received adjuvant chemotherapy or adjuvant chemo-radiotherapy

- Patients must have at least one measurable site of disease according to RECIST
(version 1.1) criteria that has not been previously irradiated. If the patient has
had previous radiation to the marker lesion(s), there must be evidence of progression
since the radiation

- Age ≥ 18 years

- Minimum of four weeks since any major surgery, completion of radiation, or completion
of all prior systemic anticancer therapy (adequately recovered from the acute
toxicities of any prior therapy)

- ECOG performance status £ 2

- Adequate bone marrow function as shown by: ANC ≥ 1.5 x 109/L, Platelets ≥ 100 x
109/L, Hgb > 9 g/dL

- Adequate liver function as shown by: serum bilirubin ≤ 1.5 x upper limit of normal
(ULN), and serum AST and ALT ≤ 2.5 x ULN. With the exception of serum AST and ALT (<
5 x ULN) if the patient has liver metastases

- Adequate renal function, serum creatinine < 2 x ULN or creatinine clearance > 50
cc/hr

- Fasting serum cholesterol ≤300 mg/dL OR ≤ 7.75 mmol/L AND fasting triglycerides ≤ 2.5
x ULN. NOTE: In cases where one or both of these thresholds are exceeded, the patient
can only be included after initiation of appropriate lipid lowering medication

- Signed informed consent

- INR and PTT < 1.5 (Anticoagulation is allowed if target INR < 1.5 on a stable dose of
warfarin or on a stable dose of LMW heparin for > 2 weeks at time of
randomization)

Exclusion Criteria:

- History of severe and uncontrolled allergic reactions to bevacizumab

- Symptomatic congestive heart failure of New York heart association Class III or IV

- Patients who have received prior treatment with an mTOR inhibitor (sirolimus,
temsirolimus, everolimus)

- DVT and hypertension controlled < 6 months

- Prior treatment with any investigational drug within the preceding 4 weeks

- Chronic treatment with systemic steroids or another immunosuppressive agent; topical
or inhaled corticosteroids are allowed

- Patients should not receive immunization with attenuated live vaccines during study
period or within 1 week of study entry

- Uncontrolled brain or leptomeningeal metastases, including patients who continue to
require glucocorticoids for brain or leptomeningeal metastases

- Other malignancies that are active at the time of enrollment/ treatment on the
protocol

- Patients who have any severe and/or uncontrolled medical conditions or other
conditions that could affect their participation in the study such as:

- unstable angina pectoris, symptomatic congestive heart failure, myocardial infarction
≤ 6 months prior to first study treatment, serious uncontrolled cardiac
arrhythmia or any other clinically significant cardiac disease

- severely impaired lung function as defined as spirometry and DLCO that is 50% of the
normal predicted value and/or O2 saturation that is 88% or less at rest on room air

- uncontrolled diabetes as defined by fasting serum glucose >1.5x ULN

- any active (acute or chronic) or uncontrolled infection/ disorders

- nonmalignant medical illnesses that are uncontrolled or whose control may be
jeopardized by the treatment with the study therapy

- known liver disease such as cirrhosis, chronic active hepatitis or chronic persistent
hepatitis

- A known history of HIV seropositivity

- Impairment of gastrointestinal function or gastrointestinal disease that may
significantly alter the absorption of RAD001 in the judgment of the investigator
(e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption
syndrome or small bowel resection)

- Patients with an active, bleeding diathesis or on oral anti-vitamin K medication
(except low dose Coumadin)

- Women who are pregnant or breast feeding, or women/men able to conceive and unwilling
to practice an effective method of birth control. (Women of childbearing potential
must have a negative urine or serum pregnancy test within 7 days prior to
administration of RAD001). Oral, implantable, or injectable contraceptives may be
affected by cytochrome P450 interactions, and are therefore not considered effective
for this study.

- Patients with a known hypersensitivity to RAD001 (everolimus) or other rapamycins
(sirolimus, temsirolimus) or to its excipients

- History of noncompliance to medical regimens

- Patients unwilling to or unable to comply with the protocol