RAD001 and AV-951 in Patients With Refractory, Metastatic Colorectal Cancer

For the Phase I component:

Inclusion Criteria

• 18 years of age or older
• Histologic confirmation of a gastrointestinal malignancy, limited to cancer of the esophagus, stomach, small bowel, liver, biliary tract, gallbladder, pancreas, large bowel, appendix, rectum and anus.
• Locally advanced or metastatic disease
• Disease that: a) has recurred or progressed following standard therapy, b) for which no standard therapy currently exists, or c) for which the subject is not a candidate for or unwilling to undergo standard therapy. There is no limit to the number of prior regimens received by the patient.
• ECOG Performance Status of 0, 1 or 2
• Life expectancy of at least 12 weeks
• Adequate organ function as outlined in the protocol
• At least 4 weeks is required from : a) previous regimen of chemotherapy, b) immunotherapy or biological therapy, c) other investigational agents, and d) radiotherapy.
• At least 4 weeks is required from treatment of bevacizumab
• At least 4 weeks is required from prior systemic hormonal therapy or treatment with strong CYP3A4 inducers or inhibitors
• If female and of child bearing potential, documentation of negative pregnancy test prior to enrollment.

Exclusion Criteria

• Prior therapy with inhibitors of mTOR or VEGFR (prior treatment with bevacizumab is allowed).
• Clinically apparent CNS metastases or carcinomatous meningitis
• Clinically significant cardiovascular disease
• Major surgery within 4 weeks of the start of study treatment or patients who have not recovered from the side effects of any major surgery.
• Active bleeding diathesis or history of Grade 2 or greater clinically significant bleeding within 3 months of enrollment
• Active infection requiring antibiotics
• Participants with a known positive history of chronic Hepatitis B viral infection or known positive HBV-DNA test are excluded.
• History of interstitial pneumonitis or severely impaired lung function defined as 88% or less O2 saturation at rest in room air
• Immunocompromise or chronic use of immunosuppressant medications
• Uncontrolled serious medical or psychiatric illness
• Subjects with non-healing wounds, active peptic ulcers, or unhealed bone fractures
• Significant proteinuria, defined as urine dipstick protein of 3+ or greater
• Concurrent malignancy (other than non-melanoma skin cancer) diagnosed within the past 3 years or any currently active malignancy
• Elevated fasting levels of the following: serum cholesterol, serum triglycerides, and serum glucose
• Patients who are pregnant or lactating
• Malabsorption, uncontrolled vomiting or diarrhea, or any disease significantly affecting gastrointestinal function that could interfere with absorption of study drugs
• Inability to swallow pills

For the phase II component, only patients with metastatic colorectal cancer will be enrolled.

For the Phase II component:

Inclusion Criteria (Phase II):

• 18 years of age or older
• Histologic confirmation of colorectal cancer
• Stage IV disease
• At least one site of disease measurable by RECIST criteria
• Receipt of or intolerance to a fluoropyrimidine (fluorouracil or capecitabine), irinotecan, oxaliplatin, bevacizumab, and a monoclonal antibody to epidermal growth factor receptor (cetuximab or panitumumab). If a patient's tumor was K-RAS mutation positive, then previous treatment with cetuximab or panitumumab is not required.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2
• Life expectancy of at least 12 weeks
• Adequate organ function as outlined in the protocol
• At least 3 weeks is required from: (a) previous regimen of chemotherapy, (b)immunotherapy or biological therapy, (c) other investigational agents, and (d) radiotherapy. Of note, concomitant radiotherapy is NOT allowed, while a patient is on protocol.
• At least 3 weeks is required from prior treatment with bevacizumab
• At least 3 weeks is required since prior systemic hormonal therapy or treatment with strong CYP3A4 inducers o