RAD001, FOLFOX and Bevacizumab in Treatment of Colorectal Carcinoma

Patient population Phase I portion: Metastatic colorectal cancer. A total of 3 patients on
each cohort. Additional 3 patients on the tolerable cohort. Total patient number: Minimum 6,
Maximum: 12 Phase II portion: Metastatic colorectal cancer: A total of 33 patients will be
treated in this portion. This will include the patients treated on the tolerable dose level
from the phase I trial. The statistical justification is indicated in the Statistics section
7.

Overall study design Phase I Study: A three cohort dose escalation will be used. Cycle
length will be 28 days.

Bevacizumab FOLFOX-6 RAD001 Cohort 1: 5 mg/ kg Q 2weeks Standard Dose FOLFOX-6 2.5 mg PO qd
Cohort 2: 5 mg/ kg Q 2weeks Standard Dose FOLFOX-6 5 mg PO qd Cohort 3: 5mg/kg Q 2 weeks
Standard Dose FOLFOX-6 10 mg PO qd

Phase II Study:

For the Phase II portion the primary endpoint is Progression Free Survival at 6 months.

Study Objectives Primary

1. To evaluate the progression free survival (PFS) for a combination of FOLFOX+
Bevacizumab + RAD001 in previously untreated metastatic or advanced colorectal cancers

2. To evaluate the safety of the combination at a daily dosing of 2.5mg RAD001, 5 mg
RAD001 or 10 mg RAD001 (Phase 1 part) Secondary

1. To study the toxicity profile of the combination 2. To study the Response Rate (RR) of
the combination 3. To determine the serum proteomic profiles of patients treated with
combination therapy (Both phase I and II portions)

Dose selection for RAD001 In phase 1 clinical studies of RAD001 as a monotherapy agent in
oncology patients, the side-effect profile is essentially mild to moderate adverse events
with a low frequency of DLT at the daily dose of 10 mg/d. Based on the PK/PD model, a daily
dose of 10mg RAD001 is assumed to provide a persistently high degree of target inhibition in
the tumor [Investigators' Brochure-Section 4.1.1.3]. In addition, preliminary data from
phase 1 studies, in which changes in molecular characteristics of tumor induced by treatment
with RAD001 at the doses of 5 and 10 mg/d were investigated, confirm the pharmacodynamic
activity predicted previously by PK/PD modeling [Investigators' Brochure-Section 4.1.1.3].
Therefore, a dose of 10 mg/d should ensure adequate drug target inhibition for most
patients, taking into consideration the known inter-patient variability in drug levels (CV
of approx 50%). In this study, we will begin with a RAD001 dose of 2.5 mg which is the
lowest dose that can be administered on a daily basis. If the dose is tolerable (<1/6 DLTs),
we will escalate to the dose of RAD001 (5 mg) and a third cohort of 10 mg. If cohort 1 is
intolerable, study will be closed without any further expansion. On any dose level, 3
patients would be enrolled. If there are 0/3 DLTs, we would be able to escalate the dose
level. If 1/3 DLTs are observed, 3 additional patients will be enrolled on the same dose
level. The intent is to escalate dose levels only if < 1/6 DLTs are observed. In case 2 or
more DLTs are observed on a particular dose level, no further dose escalation is possible.
This dose level would be deemed intolerable and the lower dose level would be expanded. The
definition of the Maximum Tolerated Dose (MTD) is the highest dose level at which RAD001 can
be combined with FOLFOX/ Bevacizumab with < 1/6 DLTs.

FOLFOX/ Bevacizumab: FOLFOX6 and Bevacizumab will be given as previously described 28.
mFOLFOX6 (oxaliplatin 85 mg/m2 IV with LV 350 mg IV over 2 hours plus FU 400 mg/m2 IV bolus
and 2,400 mg/m2continuous infusion over 46 hours every 2 weeks) will be combined with
Bevacizumab given at 5 mg/kg every 2 weeks. Dose modifications will be carried out for
chemotherapy as per the label for oxaliplatin, fluorouracil and bevacizumab.

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