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

NCT ID: NCT02008877

Last Updated: 2019-05-15

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 20 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2013-12-31
• Study Completion Date: 2018-07-31

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.

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.

Conditions

Malignant Peripheral Nerve Sheath Tumors (MPNST); Sarcoma

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

ganetespib / sirolimus

28-day cycles of ganetespib + sirolimus

Group Type: EXPERIMENTAL

ganetespib

Intervention Type: DRUG

Phase 1 Dose 1: 150 mg/m² IV on days 1, 8, and 15 intravenously over 1 hour; Phase 1 Dose 2: 200 mg/m² IV on days 1, 8, and 15 intravenously over 1 hour; Phase 2: 200 mg/m² IV on days 1, 8, and 15 intravenously over 1 hour

Sirolimus

Intervention Type: DRUG

4mg taken orally once daily on a continuous dosing schedule; Loading dose 12 mg on cycle 1 day 1 only.

Interventions

ganetespib

Phase 1 Dose 1: 150 mg/m² IV on days 1, 8, and 15 intravenously over 1 hour; Phase 1 Dose 2: 200 mg/m² IV on days 1, 8, and 15 intravenously over 1 hour; Phase 2: 200 mg/m² IV on days 1, 8, and 15 intravenously over 1 hour

Intervention Type: DRUG

Sirolimus

4mg taken orally once daily on a continuous dosing schedule; Loading dose 12 mg on cycle 1 day 1 only.

Intervention Type: DRUG

Other Intervention Names

STA-9090; Rapamycin

Eligibility 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

• Minimum Eligible Age: 16 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Synta Pharmaceuticals Corp.

INDUSTRY

Sponsor Role: collaborator

United States Department of Defense

FED

Sponsor Role: collaborator

Sarcoma Alliance for Research through Collaboration

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

AeRang Kim, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Children's National Research Institute

Brigitte Widemann, MD

Role: PRINCIPAL_INVESTIGATOR

National Cancer Institute (NCI)

Locations

Sarcoma Oncology Center

Santa Monica, California, United States

Children's National Medical Center

Washington D.C., District of Columbia, United States

University of Iowa

Iowa City, Iowa, United States

National Cancer Institute

Bethesda, Maryland, United States

University of Michigan

Ann Arbor, Michigan, United States

Washington University

St Louis, Missouri, United States

Huntsman Cancer Institute

Salt Lake City, Utah, United States

Countries

United States

References

Kim A, Lu Y, Okuno SH, Reinke D, Maertens O, Perentesis J, Basu M, Wolters PL, De Raedt T, Chawla S, Chugh R, Van Tine BA, O'Sullivan G, Chen A, Cichowski K, Widemann BC. Targeting Refractory Sarcomas and Malignant Peripheral Nerve Sheath Tumors in a Phase I/II Study of Sirolimus in Combination with Ganetespib (SARC023). Sarcoma. 2020 Jan 30;2020:5784876. doi: 10.1155/2020/5784876. eCollection 2020.

Reference Type: DERIVED

PMID: 32089640 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Related Links

http://www.sarctrials.org

SARC Website

Other Identifiers

CDMRP-NF120087

Identifier Type: OTHER_GRANT

Identifier Source: secondary_id

SARC023

Identifier Type: -

Identifier Source: org_study_id