SARC016

1. SARC016 Phase 2 study of the mTOR inhibitor RAD001 (everolimus) in combination with bevacizumab (avastin) in patients with sporadic and neurofibromatosis type 1 (NF1) related refractory malignant peripheral nerve sheath tumors PI: Brigitte Widemann, MD, National Cancer Institute Co-PI: John Perentesis, MD, University of Cincinnati

2. SARC016: Background Johannessen at al, Current Biology, 2008 • Background • NF1 inactivation results in aberrant activation of mTOR • Sirolimus halts tumor growth and prolongs survival in a genetically engineered mouse model (Nf1 p53 cis) of MPNST • Resistance develops through re-vascularization • VEGF expression  in MPNST, correlates with poor outcome

3. SARC016: Objectives • Primary Objective: • Clinical benefit rate (CR, PR, SD at ≥ 4 months, WHO) of RAD001 in combination with bevacizumab • Toxicity and safety of RAD001 and bevacizumab • Secondary Objective: • Germline NF1 mutations in patients with NF1 MPNST • NF1 mutation and inactivation in available tumor samples • Response rate sporadic and NF1 associated MPNST • Pharmacodynamics: S6K1 (p70s6K), eIF4E, eIF2, VEGF, VEGFR, AKT • 3D-MRI analysis comparison to 1 and 2-dimensional measurements • Two Stage Design: • 1ststage – 15 patients • 2nd stage – > 1 of 15 pts. respond, accrual to 25 patients total

4. SARC016: Inclusion Criteria ≥ 18 years old Unresectableor metastatic sporadic or NF1 associated high-grade MPNST (no central pathology confirmation) Progression after ≥ 1 prior cytotoxic chemotherapy regimen Note: Patients who refuse cytotoxic chemotherapy, or for whom treatment on SARC016 is felt to be in the best patient interest will also be eligible Prior therapy: ≥7 days since the completion of therapy with a biologic agent ≥ 21 days since completion of cytotoxic therapy Prior radiation: If recurrence or progression in a previously radiated field at least 4 weeks since the last dose of radiation therapy. Adequate organ function Recovered from the toxic effects of all prior to < grade 1 ECOG performance status of 0, 1, or 2 Willing to use a medically acceptable form of birth control

5. Currently receiving anticancer therapies; chronic, systemic treatment with corticosteroids or another immunosuppressive agent Immunization with attenuated live vaccines within one week of study entry or during study period Uncontrolled brain or leptomeningeal metastases Other malignancies within ≤ 3 years except for adequately treated carcinoma of the cervix or basal or squamous cell carcinomas of the skin Severe and/or uncontrolled condition that could affect study participation Prior treatment with an mTOR inhibitor for sarcoma Prior treatment with bevacizumab. Concurrent use of anti-coagulant drugs or history of coagulopathy, or bleeding diathesis Use of the following prohibited on study: Strong CYP3A4 inhibitors prohibited Seville orange, star fruit, grapefruit and their juices, and St. John’s Wort Enzyme inducing anticonvulsants SARC016: Exclusion Criteria

6. Treatment: Everolimus (2.5, 5, and 10 mg tablets): 10 mg/dose once daily continuous dosing Bevacizumab: 10 mg/kg IV every 2 weeks (day 1 and 14) 28- day cycles until disease progression or unacceptable toxicity (maximum 2 years) Dose modification for toxicity: Everolimus: Dose reductions to 5 and 2.5 mg for toxicity No dose reduction for bevacizumab Key supportive care: Patients must take some form of PCP prophylaxis while on everolimus Good oral hygiene – mucositis toxicity of everolimus Corticosteroids are permissible as premedication for blood product transfusions, or as treatment for an acute allergic reaction Patients with positive hepatitis treat prophylactically with antiviral SARC016: Treatment Plan

7. SARC016: Study Evaluations • Prior to each cycle: • PE/vitals, everolimus diary, ECOG performance status, hematology, chemistry, urinalysis, record of AEs • HBV-DNA or HCV RNA-PCR if prior hepatitis history or receiving prohylaxis or positive screening • Every other treatment cycle: • CT/MRI • Echo or MUGA scan (ONLY patients who received prior anthracylineprior) • Correlative studies if patient consented (Details in Operations Manual): • Blood sample for pro-angiogenic factors and mTOR targets: • Baseline and prior to cycles 3 and 5 • Genotyping for NF1 mutation: • Baseline only in patients with clinical diagnosis of NF1 • Tumor analysis for NF1 mutation: • All patients with frozen archival tumor sample • Volumetric MRI analysis of MPNST: • All patients with MRI scanning

8. SARC016 Patients with NF1 related or sporadic refractoryMPNST N=15 patients Schema Interim Analysis Clinical benefit rate of ≥25% additional 10 patients added • 28 day cycles of everolimus (daily dosing) + bevacizumab (day 1 and 14) Ongoing tumor assessment imagingevery 2 cycles until disease progression or unacceptable toxicity for a maximum of 2 years

9. SARC016 Status: Activated • Sponsor and Coordination: SARC • Supporter: • Novartis: everolimus • Genentech: bevacizumab • DoD: Clinical Trial award - Correlatives • Participation: • SARC sites and DoD NF Consortium • Timeline: • Activated at NCI – September 2012 • Additional sites in process of activation