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

• To determine the safety, tolerability, and maximally tolerated dose of RAD001 and AV-951 administered in combination to this patient population (Phase I). [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]
• At the maximally tolerated dose, to assess progression-free survival associated with RAD001 and AV-951 in this patient population (Phase II). [ Time Frame: 3 years ] [ Designated as safety issue: No ]

• To assess tumor response rate. [ Time Frame: 3 years ] [ Designated as safety issue: No ]
• To assess overall survival. [ Time Frame: 3 years ] [ Designated as safety issue: No ]

Research has shown that anti-angiogenic agents can be effective therapies to treat cancer. Anti-angiogenic agents target the blood vessels required for tumors to grow. Vascular endothelial growth factor (VEGF) is one of the cell pathways used for this blood vessel growth. When the investigators interfere with the VEGF pathway, the investigators inhibit this blood vessel growth which is required by tumors. One of the study drugs being used, AV-951, selectively interferes with the VEGF pathway. The second study drug being used is called RAD001. RAD001 interferes with the mTOR pathway. The mTOR pathway is another pathway involved in blood vessel and tumor cell growth. By combining these two drugs the investigators hope to slow or reverse tumor cell growth in patients whose tumors have become resistant to other therapies for their disease.

• Since we are looking for the highest dose of the study drug that can be given safely without severe or unmanageable side effects in participants with gastrointestinal malignancies, not everyone who participates will receive the same dose of the study drug. The dose will depend on the number of participants who have enrolled and how well they tolerated their doses.
• Both RAD001 and AV-951 are pills that are taken orally. Each treatment cycle lasts 4 weeks during which time participants will be taking: RAD001: once a day, every day and AV-951: once a day for 3 weeks followed by a 1 week break.
• Participants will be given a take home blood pressure machine and be instructed on how to use it. They will be asked to keep a daily blood pressure diary.
• During all cycles participants will have a physical exam (including vital signs) and be asked questions about their general health and specific questions about any problems they may be experiencing.
• Every 8 weeks the tumor will be assessed by CT scan (or imaging tests).
• Blood tests will be done every other week while the participant is on study and a urine test will be done every 4 weeks while the participant is on study.

• Drug: RAD001
  Taken orally once a day
• Drug: AV-951
  Taken orally once a day for 3 weeks followed by a 1 week break

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 or inhibitors.
• Negative pregnancy test for women of child bearing potential

Exclusion Criteria (Phase II):

• Prior therapy with inhibitors of mTOR or VEGFR (prior treatment with bevacizumab is allowed)
• Clinically apparent CNS metastases or carcinomatous meningitis, as determined by physical examination and imaging studies
• Clinically significant cardiovascular disease, defined as follows:

(A)Symptomatic congestive heart failure, (B)Symptomatic coronary artery disease or myocardial infarction within 3 months of enrollment, (C)Cardiac arrhythmias not controlled with medication, (D)Deep venous thrombosis or pulmonary embolus within the last 6 months, (E) Cerebrovascular accident within the last 12 months, (F)Poorly controlled hypertension, defined as systolic pressure > 150 mmHg or diastolic pressure > 100 mmHg documented on 2 consecutive measurements taken at least 24 hours apart, (G)Symptomatic peripheral vascular disease, defined as claudication on walking ≤

1 block

• 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. Major surgery defined as those surgeries that require general anesthesia
• Active bleeding diathesis or history of grade 2 or higher clinically significant bleeding (hemoptysis, hematemesis, hematochezia, or melena) 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 less than or equal to 88% O2 saturation at rest in room air.
• Immunocompromise or chronic use of immunosuppressant medications (prednisone ≤ 10 mg daily or the equivalent of a comparable steroid is allowed, if deemed necessary by a study investigator)
• 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 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

• Brigham and Women's Hospital
• Massachusetts General Hospital
• Beth Israel Deaconess Medical Center
• Novartis
• AVEO Pharmaceuticals, Inc.