Combination of trastuzumab and tanespimycin (17-AAG, KOS-953) is safe and active in trastuzumab-refractory HER-2-overexpressing breast cancer: A phase I dose-escalation study

Shanu Modi, Alison T Stopeck, Michael S. Gordon, David Mendelson, David B. Solit, Rochelle Bagatell, Weining Ma, Jennifer Wheler, Neal Rosen, Larry Norton, Gillian F. Cropp, Robert G. Johnson, Alison L. Hannah, Clifford A. Hudis

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Abstract

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 ≥ 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.

Original languageEnglish (US)
Pages (from-to)5410-5417
Number of pages8
JournalJournal of Clinical Oncology
Volume25
Issue number34
DOIs
Publication statusPublished - Dec 1 2007
Externally publishedYes

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ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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Combination of trastuzumab and tanespimycin (17-AAG, KOS-953) is safe and active in trastuzumab-refractory HER-2-overexpressing breast cancer : A phase I dose-escalation study. / Modi, Shanu; Stopeck, Alison T; Gordon, Michael S.; Mendelson, David; Solit, David B.; Bagatell, Rochelle; Ma, Weining; Wheler, Jennifer; Rosen, Neal; Norton, Larry; Cropp, Gillian F.; Johnson, Robert G.; Hannah, Alison L.; Hudis, Clifford A.

In: Journal of Clinical Oncology, Vol. 25, No. 34, 01.12.2007, p. 5410-5417.

Research output: Contribution to journalArticle