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

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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 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.)

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%