SARC016 B. Widemann, MD K. Cichowski, PhD

SARC016  Phase 2 study of the mTOR inhibitor everolimus (RAD001) in refractory malignant peripheral nerve sheath tumors (MPNST)

SARC016: Rationale  Poor outcome for unresectable or relapsed MPNSTs  Response to “standard chemotherapy” in chemotherapy naïve MPNST is currently being evaluated in SARC006  Development of targeted therapies is needed:  NF1 inactivation results in aberrant activation of mTOR pathway  The mTOR inhibitor sirolimus halts tumor growth and prolongs survival in a genetically engineered mouse model of MPNST  (Nf1 and p53 mutation on same chromosome, NP cis)  MTOR inhibition in human MPNST may result in response/disease stabilization

SARC016: Rationale Neurofibromin regulates mTOR pathway Johannessen at al, Proc Natl Acad Sci, 2005

SARC016: Rationale Sirolimus suppresses growth of NP cis MPNSTs in vivo Johannessen at al, Current Biology, 2008

SARC016: Objectives  Primary:  Activity of RAD001 in refractory MPNST  CR, PR, or SD at 4 months (WHO)  Secondary:  Contrast activity in sporadic versus NF1 associated MPNST  Safety and toxicity of RAD001  Asses preliminarily correlation of radiographic response and progression with changes in PD parameters including: S6K1 (p70s6K); eIF4E, eIF2  ; VEGF, VEGFR; AKT Quality of life and pain  Evaluate 3D MRI analysis to monitor response

SARC016: Design  Stratification for NF1 vs. sporadic MPNST  RAD001 p.o. (tablets) daily continuous dosing  Adults: Phase II dose 10 mg once daily  Children < 1.5 m 2 BSA: 5 mg/m 2 BSA once daily  One cycle = 28 days  Toxicity monitoring:  H&P, pulsox, BP,CBC/Diff, chem 20, blood lipids, glc.  Response evaluation:  MRI/CT prior to every odd cycle (1, 3, 5, etc.)

SARC016: Statistical Considerations  Stratification for NF1 versus sporadic MPNST  Target response rate ≥30%, rule out 5%  Response = CR, PR, SD at 4 months  Enrollment of 10 pts. on each stratum:  If ≥ 1 of 10 pts respond expand enrollment to 20 pts  If ≥ 4 of 20 pts respond in a stratum, RAD001 will be considered worthy for further exploration  Power 94.5%, one sided alpha 1.5%

SARC016: Statistical Considerations  Stratification for NF1 versus sporadic MPNST  Target response rate ≥20%, rule out 5%  Response = CR, PR, SD at 4 months  Enrollment of 20 pts. on each stratum:  If ≥ 1 of 20 respond expand enrollment to 40 pts  If ≥ 5 of 40 respond in a stratum, RAD001 will be considered worthy for further exploration  Significance level 5%, power 90%