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SARC016

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

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SARC016

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  1. SARC016 B. Widemann, MD K. Cichowski, PhD

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

  3. 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

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

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

  6. 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

  7. 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 m2 BSA: 5 mg/m2 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.)

  8. 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%

  9. 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%

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