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, 15 Ganetespib IV over 1 hour

Days 1-28 Sirolimus PO once daily

Day 28 End 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