SARC023: Ganetespib and Sirolimos in Patients With MPNST (Malignant Peripheral Nerve Sheath Tumors)

Previously, no targeted agents have been able to cause tumor regression in a genetically
engineered MPNST mouse model or human MPNST. Recently published data from Dr. Cichowski's
laboratory demonstrated using Hsp90 inhibitors to enhance endoplasmic reticulum stress
coupled with the mammalian target of rapamycin (mTOR) inhibitor sirolimus led to dramatic
tumor shrinkage in a transgenic MPNST mouse model, which correlated with profound damage to
the endoplasmic reticulum and cell death. Ganetespib is a novel, injectable, small molecule
inhibitor of Hsp90 and is currently being investigated in adults with a broad range of tumor
types with a favorable safety profile and promising early results. Ganetespib has been
studied in preclinical in vivo models with a variety of targeted agents with no marked
apparent pharmacological interactions. Sirolimus is a commercially available orally
administered mTOR inhibitor and is the active metabolite of temsirolimus, which is FDA
approved agent for advanced metastatic renal cell carcinoma. Sirolimus has been studied and
tolerated in combination with multiple cytotoxic and targeted agents in a variety of tumor
types. Based on strong preclinical rationale, the investigators hypothesize that ganetespib
in combination with sirolimus will cause tumor regression in patients with refractory MPNSTs.

The investigators propose a multi-institutional open label phase I/II trial of ganetespib in
combination with sirolimus in patients with refractory sarcoma including MPNST. Hsp90
inhibitors and mTOR inhibitors have also both demonstrated benefit in a variety of
preclinical bone and soft tissue sarcoma models. The investigators hypothesize that these
agents that work on separate and potentially synergistic pathways will also be beneficial for
other refractory bone and soft tissue sarcomas. Thus, the phase I component will be open to
patients with refractory sarcomas, which will also expedite enrollment. Upon determination of
the recommended dosing, a phase II study will be conducted. The phase II study population
will be limited to patients with a diagnosis of MPNST.

Inclusion Criteria:

- Patients ≥ 16 years old

- Patients with unresectable or metastatic histologically confirmed sporadic or NF1
associated high grade MPNST

- Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2

- Patients must have at least 1 measurable tumor

- Patients must have fully recovered from the acute toxic effects of all prior
anti-cancer therapy (toxicity < grade 2)

- Must be able to swallow whole pills

- Adequate organ function

- Normal fasting cholesterol and triglycerides

- May be on cholesterol medications

Exclusion Criteria:

- Patients receiving current treatment with corticosteroids or another
immunosuppressive. Topical or inhaled corticosteroids are allowed.

- Uncontrolled brain or leptomeningeal metastases, including patients who continue to
require glucocorticoids for brain or leptomeningeal metastases

- Symptomatic congestive heart failure

- Severely impaired lung function

- Significant vascular disease

- Uncontrolled diabetes

- Active (acute or chronic) or uncontrolled severe infections hepatitis

- Impairment of gastrointestinal function

- Patients with an active, bleeding diathesis or significant coagulopathy

- Use of cytochrome P450 isoenzyme 3A4 (CYP3A4)/ CYP2C19 substrates