{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T02:25:07Z","timestamp":1790130307660,"version":"4.0.1"},"reference-count":36,"publisher":"Wiley","license":[{"start":{"date-parts":[[2020,1,31]],"date-time":"2020-01-31T00:00:00Z","timestamp":1580428800000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["W81XWH-13-1-0072"],"award-info":[{"award-number":["W81XWH-13-1-0072"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Sarcoma"],"published-print":{"date-parts":[[2020,1,31]]},"abstract":"<jats:p><jats:italic>Purpose<\/jats:italic>. Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive soft tissue sarcomas. Combining Hsp90 inhibitors to enhance endoplasmic reticulum stress with mTOR inhibition results in dramatic MPNST shrinkage in a genetically engineered MPNST mouse model. Ganetespib is an injectable potent small molecule inhibitor of Hsp90. Sirolimus is an oral mTOR inhibitor. We sought to determine the safety, tolerability, and recommended dose of ganetespib and sirolimus in patients with refractory sarcomas and assess clinical benefits in patients with unresectable\/refractory MPNSTs. <jats:italic>Patients and Methods<\/jats:italic>. In this multi-institutional, open-label, phase 1\/2 study of ganetespib and sirolimus, patients \u226516 years with histologically confirmed refractory sarcoma (phase 1) or MPNST (phase 2) were eligible. A conventional 3\u2009+\u20093 dose escalation design was used for phase 1. Pharmacokinetic and pharmacodynamic measures were evaluated. Primary objectives of phase 2 were to determine the clinical benefit rate (CBR) of this combination in MPNSTs. Patient-reported outcomes assessed pain. <jats:italic>Results<\/jats:italic>. Twenty patients were enrolled (10 per phase). Toxicities were manageable; most frequent non-DLTs were diarrhea, elevated liver transaminases, and fatigue. The recommended dose of ganetespib was 200\u2009mg\/m<jats:sup>2<\/jats:sup> intravenously on days 1, 8, and 15 with sirolimus 4\u2009mg orally once daily with day 1 loading dose of 12\u2009mg. In phase 1, one patient with leiomyosarcoma achieved a sustained partial response. In phase 2, no responses were observed. The median number of cycles treated was 2 (1\u20134). Patients did not meet the criteria for clinical benefit as defined per protocol. Pain ratings decreased or were stable. <jats:italic>Conclusion<\/jats:italic>. Despite promising preclinical rationale and tolerability of the combination therapy, no responses were observed, and the study did not meet parameters for further evaluation in MPNSTs. This trial was registered with (<jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/clinicaltrials.gov\/ct2\/show\/NCT02008877\">NCT02008877<\/jats:ext-link>).<\/jats:p>","DOI":"10.1155\/2020\/5784876","type":"journal-article","created":{"date-parts":[[2020,1,31]],"date-time":"2020-01-31T18:34:18Z","timestamp":1580495658000},"page":"1-8","source":"Crossref","is-referenced-by-count":59,"title":["Targeting Refractory Sarcomas and Malignant Peripheral Nerve Sheath Tumors in a Phase I\/II Study of Sirolimus in Combination with Ganetespib (SARC023)"],"prefix":"10.1155","volume":"2020","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7813-5568","authenticated-orcid":true,"given":"AeRang","family":"Kim","sequence":"first","affiliation":[{"name":"Children\u2019s National Medical Center, 111 Michigan Ave., NW, Washington, DC 20010, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yao","family":"Lu","sequence":"additional","affiliation":[{"name":"SARC Statistics, Weill Cornell Medicine Healthcare and Policy Research, 602 East 67th Street, New York, NY 10065, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1297-6946","authenticated-orcid":true,"given":"Scott H.","family":"Okuno","sequence":"additional","affiliation":[{"name":"Mayo Clinic, 200 First St., SW, Rochester, MN 55905, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Denise","family":"Reinke","sequence":"additional","affiliation":[{"name":"SARC, 24 Frank Lloyd Wright Drive, Ann Arbor, MI 48105, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oph\u00e9lia","family":"Maertens","sequence":"additional","affiliation":[{"name":"Children's Hospital of Philadelphia, Univeristy of Pennsylvania, 3501 Civic Center Boulevard, 19104 Philadelphia, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Perentesis","sequence":"additional","affiliation":[{"name":"Cincinnati Children's Hospital & Uinviersity of Cincinnati, 3333 Burnet Ave., Cincinnati, OH 45229, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mitali","family":"Basu","sequence":"additional","affiliation":[{"name":"Cincinnati Children's Hospital & Uinviersity of Cincinnati, 3333 Burnet Ave., Cincinnati, OH 45229, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pamela L.","family":"Wolters","sequence":"additional","affiliation":[{"name":"Pediatric Oncology Branch, National Cancer Institute, 10 Center Drive, Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"De Raedt","sequence":"additional","affiliation":[{"name":"Children's Hospital of Philadelphia, Univeristy of Pennsylvania, 3501 Civic Center Boulevard, 19104 Philadelphia, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sant","family":"Chawla","sequence":"additional","affiliation":[{"name":"Sarcoma Oncology Center, 2811 Wilshire Blvd, Santa Monica, CA 90403, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rashmi","family":"Chugh","sequence":"additional","affiliation":[{"name":"University of Michigan, 1500 E. 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