SARC023 Phase I/II trial of ganetespib, an heat shock protein 90 inhibitor in combination with the mTOR inhibitor sirolimus for patients with unresectable or metastatic malignant peripheral nerve sheath tumor Principal Investigator: AeRang Kim, MD, PhD Children’s National Medical Center Co-Principal Investigator: Brigitte Widemann, MD National Cancer Institute, National Institutes of Health

SARC023  SARC  Sponsor and coordinating center  Department of Defense: Clinical Trial Award  Supporter  Synta  Providing ganetespib  Sirolimus  Purchase commercial grade

SARC023  Background  Studies in a transgenic NF1 MPNST mouse model demonstrated that enhancing ER stress using an HSP90 inhibitor coupled with sirolimus led to first time dramatic tumor shrinkage. DeRaedt T….Cichowski, Cancer Cell 2011

Schema  Cycles will be 28 days until progression or unacceptable toxicity for a maximum of 1 year (13 cycles)  Response evaluations every 2 cycles Treatment Days 1, 8, 15Ganetespib IV over 1 hour Days 1-28Sirolimus PO once daily Day 28End of Cycle

Phase I Primary Objectives  Phase I – up to 18 patients  Assess safety, tolerability, and maximum tolerated/recommended dose of ganetespib in combination with sirolimus  Patients with unresectable or metastatic sporadic or NF1 associated high grade MPNST AND other refractory or relapsed sarcomas  Limited dose escalation (2 dose levels). Once MTD/RP2D determined  Proceed to Phase II

Phase II Primary Objectives  Phase II – up to 20 patients  To determine the activity of ganetespib in combination with sirolimus  Patients with unresectable or metastatic histologically confirmed sporadic or NF1 associated high grade MPNST  A Simon’s optimal two-stage Phase II design; if > 1 of 10 patients respond, accrual will continue until a total of 20 patients have been enrolled

Secondary Objectives  Phase I:  To describe the plasma pharmacokinetic profile of ganetespib and sirolimus when administered in combination therapy  Phase I/II:  To determine changes in pharmacodynamic parameters including:  phospho-S6  phosphorylated eIF2 alpha  Akt phosphorylation  Hsp70  G6PD

Secondary Objectives  Phase I/II continued:  To assess:  Patient-reported pain severity  Impact of pain on daily activities before and during treatment with ganetespib and sirolimus and to correlate with changes in clinical and radiologic outcome  To evaluate the utility of 3-D MRI

Inclusion Criteria  Patients ≥ 18 years old with unresectable, recurrent, or metastatic sarcoma of a multitude of sub-types  ECOG performance status of 0, 1, or 2  Patients must have > 1 measurable tumor  Patients must have fully recovered from the acute toxic effects of all prior anti- cancer therapy (toxicity < grade 2)  Adequate organ function

Study Status  DoD award received  Contracting for study drug  In process with Synta; anticipated completion November 2013  Limited centers for phase 1 portion  Anticipate 5 sites  Phase 2 portion  5 additional sites to be activated (10 total)  NCI IRB approval obtained  eview with DoD

Study Status  NCI IRB approval obtained  Under review with DoD  Once DoD approval obtained, will go to selected sites for individual institution IRB review