Clinical trial NCT02008877: SARC023: Ganetespib and Sirolimus in Patients With MPNST (Malignant Peripheral Nerve Sheath Tumors)
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 type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Malignant Peripheral Nerve Sheath Tumors (MPNST)
Sarcoma
Keywords: Malignant Peripheral Nerve Sheath Tumors
MPNST
Sarcoma
Ganetespib
Sirolimus
mTOR inhibitor
Heat shock protein
Hsp90
Lead sponsor: Sarcoma Alliance for Research through Collaboration
Sponsor class: OTHER
Collaborators: name: Synta Pharmaceuticals Corp.
name: United States Department of Defense
First posted: 2013-12-11
Enrollment: 20
Sex: ALL
Minimum age (years): 16
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Number of Dose Limiting Toxicities of Ganetespib When Administered in Combination With Sirolimus.
timeFrame: Toxicities will be evaluated over the first treatment cycle (each cycle=28 days)
measure: Clinical Benefit of Ganetespib in Combination With Sirolimus
timeFrame: Response evaluations will be performed after every 2 treatment cycles (each cycle=28 days)
Secondary outcomes:
measure: Change in Plasma Pharmacokinetic Profile of Ganetespib and Sirolimus When Administered in Combination-Observed Maximum Plasma Concentration (Cmax)
timeFrame: Pre-therapy levels drawn at baseline and pharmacokinetic analysis occurs on Cycle 1 Day 15
measure: Changes in Pharmacodynamic Parameters in Peripheral Blood Mononuclear Cells
timeFrame: Baseline and Cycle 1 Day 15
measure: Patient-reported Pain Severity and the Impact of Pain on Daily Activities
timeFrame: Baseline and prior to Cycle 3
measure: Utility of Three-dimensional MRI (3D-MRI) Analysis in Comparison to 1-dimensional and 2-dimensional Measurements
timeFrame: 4 months
measure: Plasma Pharmacokinetic Profile of Ganetespib When Administered in Combination With Sirolimus
timeFrame: Cycle 1 Day 15
measure: Determine Maximum Tolerated Dose (MTD)/Recommended Dose (RD) of Ganetespib
timeFrame: Phase 1 of study
Other outcomes:
Locations:
city: Santa Monica
country: United States
facility: Sarcoma Oncology Center
state: California
city: Washington
country: United States
facility: Children's National Medical Center
state: District of Columbia
city: Iowa City
country: United States
facility: University of Iowa
state: Iowa
city: Bethesda
country: United States
facility: National Cancer Institute
state: Maryland
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
city: Saint Louis
country: United States
facility: Washington University
state: Missouri
city: Salt Lake City
country: United States
facility: Huntsman Cancer Institute
state: Utah
Study officials:
affiliation: Children's National
name: AeRang Kim, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: National Cancer Institute (NCI)
name: Brigitte Widemann, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.