SARC023: Ganetespib and Sirolimos in Patients With MPNST (Malignant Peripheral Nerve Sheath Tumors)
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| ClinicalTrials.gov Identifier: NCT02008877 |
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Recruitment Status :
Completed
First Posted : December 11, 2013
Last Update Posted : July 17, 2018
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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 |
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 Type : | Interventional (Clinical Trial) |
| Actual Enrollment : | 20 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 |
| Actual Primary Completion Date : | April 2018 |
| Actual Study Completion Date : | July 2018 |
| Arm | Intervention/treatment |
|---|---|
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Experimental: ganetespib / sirolimus
28-day cycles of ganetespib + sirolimus
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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 |
- 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). ]
- 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.
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| Ages Eligible for Study: | 16 Years and older (Child, Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
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
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02008877
| 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 | |
| Principal Investigator: | AeRang Kim, MD, PhD | Children's National | |
| Principal Investigator: | Brigitte Widemann, MD | National Cancer Institute (NCI) |
Additional Information:
| 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 Key Record Dates |
| Last Update Posted: | July 17, 2018 |
| Last Verified: | November 2017 |
Keywords provided by Sarcoma Alliance for Research through Collaboration:
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Malignant Peripheral Nerve Sheath Tumors MPNST Sarcoma Ganetespib |
Sirolimus mTOR inhibitor Heat shock protein Hsp90 |
Additional relevant MeSH terms:
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Sarcoma Nerve Sheath Neoplasms 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 Neurofibroma Sirolimus Everolimus Anti-Bacterial Agents Anti-Infective Agents Antibiotics, Antineoplastic Antineoplastic Agents Antifungal Agents Immunosuppressive Agents Immunologic Factors |