PURPOSE: 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. PATIENTS AND METHODS: 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. RESULTS: Twenty-five patients were enrolled onto four tanespimycin dose levels: 225 (n = 4), 300 (n = 3), 375 (n = 8), and 450 mg/m2 (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/m2); more than 2-week delay for thrombocytopenia (450 mg/m2). 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 > or = 4 months, n = 4). Tumor regressions were seen only in patients with human epidermal growth factor receptor 2 (HER-2)-positive metastatic breast cancer. CONCLUSION: 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.
PURPOSE: 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. PATIENTS AND METHODS: 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. RESULTS: Twenty-five patients were enrolled onto four tanespimycin dose levels: 225 (n = 4), 300 (n = 3), 375 (n = 8), and 450 mg/m2 (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/m2); more than 2-week delay for thrombocytopenia (450 mg/m2). 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 > or = 4 months, n = 4). Tumor regressions were seen only in patients with humanepidermal growth factor receptor 2 (HER-2)-positive metastatic breast cancer. CONCLUSION: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.
Authors: Tineke E Buffart; Beatriz Carvalho; Nicole C T van Grieken; Wessel N van Wieringen; Marianne Tijssen; Elma Meershoek-Klein Kranenbarg; Henk M W Verheul; Heike I Grabsch; Bauke Ylstra; Cornelis J H van de Velde; Gerrit A Meijer Journal: Oncologist Date: 2012-04-24
Authors: Pavel A Tsaytler; Jeroen Krijgsveld; Soenita S Goerdayal; Stefan Rüdiger; Maarten R Egmond Journal: Cell Stress Chaperones Date: 2009-04-26 Impact factor: 3.667
Authors: Edward B Garon; Richard S Finn; Habib Hamidi; Judy Dering; Sharon Pitts; Naeimeh Kamranpour; Amrita J Desai; Wylie Hosmer; Susan Ide; Emin Avsar; Michael Rugaard Jensen; Cornelia Quadt; Manway Liu; Steven M Dubinett; Dennis J Slamon Journal: Mol Cancer Ther Date: 2013-03-14 Impact factor: 6.261
Authors: Joleen Hubbard; Charles Erlichman; David O Toft; Rui Qin; Bridget A Stensgard; Sara Felten; Cynthia Ten Eyck; Gretchen Batzel; S Percy Ivy; Paul Haluska Journal: Invest New Drugs Date: 2010-01-15 Impact factor: 3.850