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

Sarcoma Alliance for Research through Collaboration

Status and phase

Completed

Phase 2

Phase 1

Conditions

Malignant Peripheral Nerve Sheath Tumors (MPNST)

Sarcoma

Treatments

Drug: ganetespib

Drug: Sirolimus

Study type

Interventional

Funder types

Other

Industry

Other U.S. Federal agency

Identifiers

NCT02008877

SARC023

CDMRP-NF120087 (Other Grant/Funding Number)

Details and patient eligibility

About

Phase 1: To assess the safety, tolerability, and maximum tolerated dose (MTD)/ recommended dose of ganetespib when administered in combination with sirolimus in patients with refractory or relapsed sarcomas including unresectable or metastatic sporadic or neurofibromatosis type 1 (NF1) associated MPNST. Phase I enrollment has been closed.

Phase 2: To determine the clinical benefit of ganetespib in combination with sirolimus for patients with unresectable or metastatic sporadic or NF1 associated MPNST.

Full description

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.

Enrollment

20 patients

Sex

All

Ages

16+ years old

Volunteers

No Healthy Volunteers

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