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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
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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
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
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 • eviewwith 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