{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T00:12:26Z","timestamp":1791159146514,"version":"4.1.0"},"reference-count":21,"publisher":"American Society of Clinical Oncology (ASCO)","issue":"34","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCO"],"published-print":{"date-parts":[[2007,12,1]]},"abstract":"<jats:sec><jats:title>Purpose<\/jats:title><jats:p> This phase I study examined whether a heat shock protein (Hsp) 90 inhibitor tanespimycin (17-AAG; KOS-953) could be administered safely in combination with trastuzumab at a dose that inhibits Hsp90 function in vivo in lymphocytes. <\/jats:p><\/jats:sec><jats:sec><jats:title>Patients and Methods<\/jats:title><jats:p> Patients with an advanced solid tumor progressing during standard therapy were eligible. Patients were treated with weekly trastuzumab followed by intravenous tanespimycin, assessed in escalating dose levels. <\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p> Twenty-five patients were enrolled onto four tanespimycin dose levels: 225 (n = 4), 300 (n = 3), 375 (n = 8), and 450 mg\/m<jats:sup>2<\/jats:sup> (n = 10). Dose-limiting toxicity (DLT) was observed at the third and fourth cohort (1 patient each): more than 2-week delay for grade 4 fatigue\/grade 2 nausea and anorexia (375 mg\/m<jats:sup>2<\/jats:sup>); more than 2-week delay for thrombocytopenia (450 mg\/m<jats:sup>2<\/jats:sup>). Drug-related grade 3 toxicity included emesis, increased ALT, hypersensitivity reactions (two patients each), and drug-induced thrombocytopenia (n = 1). Common mild to moderate toxicities included fatigue, nausea, diarrhea, emesis, headache, rash\/pruritus, increased AST\/ALT, and anorexia. Pharmacokinetic analysis demonstrated no difference in tanespimycin kinetics with or without trastuzumab. Pharmacodynamic testing showed reactive induction of Hsp70 (a marker of Hsp90 inhibition) in lymphocytes at all dose levels. Antitumor activity was noted (partial response, n = 1; minor response, n = 4; stable disease \u2265 4 months, n = 4). Tumor regressions were seen only in patients with human epidermal growth factor receptor 2 (HER-2)-positive metastatic breast cancer. <\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p> Tanespimycin plus trastuzumab is well tolerated and has antitumor activity in patients with HER-2+ breast cancer whose tumors have progressed during treatment with trastuzumab. These data suggest that Hsp90 function can be inhibited in vivo to a degree sufficient to cause inhibition of tumor growth. <\/jats:p><\/jats:sec>","DOI":"10.1200\/jco.2007.11.7960","type":"journal-article","created":{"date-parts":[[2007,11,29]],"date-time":"2007-11-29T23:28:17Z","timestamp":1196378897000},"page":"5410-5417","source":"Crossref","is-referenced-by-count":282,"title":["Combination of Trastuzumab and Tanespimycin (17-AAG, KOS-953) Is Safe and Active in Trastuzumab-Refractory HER-2\u2013Overexpressing Breast Cancer: A Phase I Dose-Escalation Study"],"prefix":"10.1200","volume":"25","author":[{"given":"Shanu","family":"Modi","sequence":"first","affiliation":[{"name":"From the Memorial Sloan-Kettering Cancer Center, New York, NY; Arizona Cancer Center, Tucson\/Scottsdale, AZ; and Kosan Biosciences Inc, Hayward, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alison T.","family":"Stopeck","sequence":"additional","affiliation":[{"name":"From the Memorial Sloan-Kettering Cancer Center, New York, NY; Arizona Cancer Center, Tucson\/Scottsdale, AZ; and Kosan Biosciences Inc, Hayward, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael S.","family":"Gordon","sequence":"additional","affiliation":[{"name":"From the Memorial Sloan-Kettering Cancer Center, New York, NY; Arizona Cancer Center, Tucson\/Scottsdale, AZ; and Kosan Biosciences Inc, Hayward, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Mendelson","sequence":"additional","affiliation":[{"name":"From the Memorial Sloan-Kettering Cancer Center, New York, NY; Arizona Cancer Center, Tucson\/Scottsdale, AZ; and Kosan Biosciences Inc, Hayward, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David B.","family":"Solit","sequence":"additional","affiliation":[{"name":"From the Memorial Sloan-Kettering Cancer Center, New York, NY; Arizona Cancer Center, Tucson\/Scottsdale, AZ; and Kosan Biosciences Inc, Hayward, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rochelle","family":"Bagatell","sequence":"additional","affiliation":[{"name":"From the Memorial Sloan-Kettering Cancer Center, New York, NY; Arizona Cancer Center, Tucson\/Scottsdale, AZ; and Kosan Biosciences Inc, Hayward, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weining","family":"Ma","sequence":"additional","affiliation":[{"name":"From the Memorial Sloan-Kettering Cancer Center, New York, NY; Arizona Cancer Center, Tucson\/Scottsdale, AZ; and Kosan Biosciences Inc, Hayward, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer","family":"Wheler","sequence":"additional","affiliation":[{"name":"From the Memorial Sloan-Kettering Cancer Center, New York, NY; Arizona Cancer Center, Tucson\/Scottsdale, AZ; and Kosan Biosciences Inc, Hayward, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neal","family":"Rosen","sequence":"additional","affiliation":[{"name":"From the Memorial Sloan-Kettering Cancer Center, New York, NY; Arizona Cancer Center, Tucson\/Scottsdale, AZ; and Kosan Biosciences Inc, Hayward, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Larry","family":"Norton","sequence":"additional","affiliation":[{"name":"From the Memorial Sloan-Kettering Cancer Center, New York, NY; Arizona Cancer Center, Tucson\/Scottsdale, AZ; and Kosan Biosciences Inc, Hayward, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gillian F.","family":"Cropp","sequence":"additional","affiliation":[{"name":"From the Memorial Sloan-Kettering Cancer Center, New York, NY; Arizona Cancer Center, Tucson\/Scottsdale, AZ; and Kosan Biosciences Inc, Hayward, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert G.","family":"Johnson","sequence":"additional","affiliation":[{"name":"From the Memorial Sloan-Kettering Cancer Center, New York, NY; Arizona Cancer Center, Tucson\/Scottsdale, AZ; and Kosan Biosciences Inc, Hayward, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alison L.","family":"Hannah","sequence":"additional","affiliation":[{"name":"From the Memorial Sloan-Kettering Cancer Center, New York, NY; Arizona Cancer Center, Tucson\/Scottsdale, AZ; and Kosan Biosciences Inc, Hayward, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clifford A.","family":"Hudis","sequence":"additional","affiliation":[{"name":"From the Memorial Sloan-Kettering Cancer Center, New York, NY; Arizona Cancer Center, Tucson\/Scottsdale, AZ; and Kosan Biosciences Inc, Hayward, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"233","reference":[{"key":"R1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.93.25.14536"},{"key":"R2","doi-asserted-by":"publisher","DOI":"10.2174\/156802606777812068"},{"key":"R3","doi-asserted-by":"publisher","DOI":"10.1517\/14712598.2.1.3"},{"key":"R4","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.91.18.8324"},{"key":"R5","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1205184"},{"key":"R6","unstructured":"Solit DB, Zheng FF, Drobnjak M, et al: 17-allylamino-17-demethoxygeldanamycin induces the degradation of androgen receptor and HER-2\/neu and inhibits the growth of prostate cancer xenografts. Clin Cancer Res 8:986,2002-993,"},{"key":"R7","unstructured":"Solit DB, Basso AD, Olshen AB, et al: Inhibition of heat shock protein 90 function downregulates akt kinase and sensitizes tumors to taxol. Cancer Res 63:2139,2003-2144,"},{"key":"R8","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-05-0518"},{"key":"R9","doi-asserted-by":"publisher","DOI":"10.1097\/00001813-200404000-00011"},{"key":"R10","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-06-1015"},{"key":"R11","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2005.00.612"},{"key":"R12","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-04-2322"},{"key":"R13","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2005.12.085"},{"key":"R14","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-06-1863"},{"key":"R15","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2005.09.119"},{"key":"R18","doi-asserted-by":"publisher","DOI":"10.1159\/000055399"},{"key":"R19","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/92.3.205"},{"key":"R20","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2003.07.984"},{"key":"R21","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-03-0463"},{"key":"R22","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa064320"},{"key":"R23","doi-asserted-by":"publisher","DOI":"10.1021\/cb600224w"}],"container-title":["Journal of Clinical Oncology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/ascopubs.org\/doi\/pdfdirect\/10.1200\/JCO.2007.11.7960","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,5,25]],"date-time":"2022-05-25T20:13:52Z","timestamp":1653509632000},"score":1,"resource":{"primary":{"URL":"https:\/\/ascopubs.org\/doi\/10.1200\/JCO.2007.11.7960"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2007,12,1]]},"references-count":21,"journal-issue":{"issue":"34","published-print":{"date-parts":[[2007,12,1]]}},"alternative-id":["10.1200\/JCO.2007.11.7960"],"URL":"https:\/\/doi.org\/10.1200\/jco.2007.11.7960","relation":{},"ISSN":["0732-183X","1527-7755"],"issn-type":[{"value":"0732-183X","type":"print"},{"value":"1527-7755","type":"electronic"}],"subject":[],"published":{"date-parts":[[2007,12,1]]}}}