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

Study Description

Go to 

Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Malignant Peripheral Nerve Sheath Tumors (MPNST); Sarcoma	Drug: ganetespib; Drug: Sirolimus	Phase 1; Phase 2

Detailed 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.

Study Design

Go to 

Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	38 participants
Intervention Model:	Single Group Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	A Phase I/II Trial of Ganetespib in Combination With the mTOR Inhibitor Sirolimus for Patients With Recurrent or Refractory Sarcomas Including Unresectable or Metastatic Malignant Peripheral Nerve Sheath Tumors
Study Start Date :	December 2013
Estimated Primary Completion Date :	April 2018
Estimated Study Completion Date :	April 2018

Arms and Interventions

Go to 

Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Arm	Intervention/treatment
Experimental: ganetespib / sirolimus; 28-day cycles of ganetespib + sirolimus	Drug: ganetespib; 200 mg/m² IV on days 1, 8, and 15 intravenously over 1 hour; Other Name: STA-9090 Drug: Sirolimus; 2mg taken orally once daily on a continuous dosing schedule; Loading dose 12 mg on cycle 1 day 1 only.; Other Name: Rapamycin

Outcome Measures

Go to 

Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Primary Outcome Measures :

1. Grade the toxicity of ganetespib when administered in combination with sirolimus. [ Time Frame: Toxicities will be evaluated each 28 day cycle for up to 1 year (13 cycles). ]

Secondary Outcome Measures :

1. Clinical benefit of combined study drugs. [ Time Frame: 4 months ]
   Assessed using the World Health Organization (WHO) criteria. Tumor assessments will be obtained every 2 cycles. Clinical benefit is defined as stable disease, Partial Response (PR), Complete Response (CR). For patients who experience progression by WHO but in the opinion of the treating investigator are deriving benefit from therapy and have not otherwise met off treatment or off study criteria, may continue on treatment as long as patient has not met progression by RECIST 1.1.

Eligibility Criteria

Go to 

Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Ages Eligible for Study:	16 Years and older (Child, Adult, Senior)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

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

Contacts and Locations

Go to 

Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Locations

United States, California
Sarcoma Oncology Center
Santa Monica, California, United States, 90403
United States, District of Columbia
Children's National Medical Center
Washington, District of Columbia, United States, 20010
United States, Iowa
University of Iowa
Iowa City, Iowa, United States, 52242
United States, Maryland
National Cancer Institute
Bethesda, Maryland, United States, 20892
United States, Michigan
University of Michigan
Ann Arbor, Michigan, United States, 48109
United States, Missouri
Washington University
Saint Louis, Missouri, United States, 63130
United States, Utah
Huntsman Cancer Institute
Salt Lake City, Utah, United States, 84112

Sponsors and Collaborators

Sarcoma Alliance for Research through Collaboration

Synta Pharmaceuticals Corp.

United States Department of Defense

Investigators

Principal Investigator:	AeRang Kim, MD, PhD	Children's National
Principal Investigator:	Brigitte Widemann, MD	National Cancer Institute (NCI)

More Information

Go to 

Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Additional Information:

SARC Website 

Responsible Party:	Sarcoma Alliance for Research through Collaboration
ClinicalTrials.gov Identifier:	NCT02008877 History of Changes
Other Study ID Numbers:	SARC023; CDMRP-NF120087 ( Other Grant/Funding Number: Department of Defense )
First Posted:	December 11, 2013
Last Update Posted:	November 14, 2017
Last Verified:	November 2017

Keywords provided by Sarcoma Alliance for Research through Collaboration:

Malignant Peripheral Nerve Sheath Tumors; MPNST; Sarcoma; Ganetespib	Sirolimus; mTOR inhibitor; Heat shock protein; Hsp90

Additional relevant MeSH terms:

Sarcoma; Nerve Sheath Neoplasms; Neurofibroma; Neurilemmoma; Neurofibrosarcoma; Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Nerve Tissue; Peripheral Nervous System Neoplasms; Nervous System Neoplasms; Nervous System Diseases; Peripheral Nervous System Diseases; Neuromuscular Diseases; Neuroendocrine Tumors	Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neuroma; Fibrosarcoma; Neoplasms, Fibrous Tissue; Neoplasms, Connective Tissue; Sirolimus; Everolimus; Anti-Bacterial Agents; Anti-Infective Agents; Antibiotics, Antineoplastic; Antineoplastic Agents; Antifungal Agents; Immunosuppressive Agents; Immunologic Factors