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  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 Johannessen at al, Current Biology, 2008

3.  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:  1 st stage – 15 patients  2 nd stage – > 1 of 15 pts. respond, accrual to 25 patients total SARC016: Objectives

4. SARC016: Inclusion Criteria  ≥ 18 years old  Unresectable or 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 anthracyline prior)  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. Patients with NF1 related or sporadic refractory MPNST N=15 patients 28 day cycles of everolimus (daily dosing) + bevacizumab (day 1 and 14) Interim Analysis Clinical benefit rate of ≥25% additional 10 patients added Ongoing tumor assessment imaging every 2 cycles until disease progression or unacceptable toxicity for a maximum of 2 years SARC016 Schema

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