SARC023

1. 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: AeRangKim, MD, PhD Children’s National Medical Center Co-Principal Investigator: Brigitte Widemann, MD National Cancer Institute, National Institutes of Health

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

3. 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

4. Schema • Cycles will be 28 days until progression or unacceptable toxicity for a maximum of 1 year (13 cycles) • Response evaluations every 2 cycles

5. 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

6. 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

7. 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

8. 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

9. 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

10. 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 • eviewwith DoD

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