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 Journal Article


Authors: Modi, S.; Stopeck, A. T.; Gordon, M. S.; Mendelson, D.; Solit, D. B.; Bagatell, R.; Ma, W.; Wheler, J.; Rosen, N.; Norton, L.; Cropp, G. F.; Johnson, R. G.; Hannah, A. L.; Hudis, C. A.
Article Title: 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
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. © 2007 by American Society of Clinical Oncology.
Keywords: adult; clinical article; controlled study; treatment response; aged; aged, 80 and over; middle aged; unclassified drug; clinical trial; fatigue; neutropenia; advanced cancer; area under the curve; cancer growth; diarrhea; drug safety; drug withdrawal; monotherapy; side effect; solid tumor; neurotoxicity; antineoplastic agent; anorexia; drug inhibition; gene overexpression; metastasis; multiple cycle treatment; breast cancer; anemia; bone marrow suppression; bleeding; nausea; thrombocytopenia; vomiting; antineoplastic combined chemotherapy protocols; qt prolongation; epidermal growth factor receptor 2; combination chemotherapy; in vivo study; antineoplastic activity; tumor regression; drug effect; dose-response relationship, drug; drug resistance, neoplasm; breast neoplasms; abdominal pain; drug dose escalation; febrile neutropenia; injection site reaction; loading drug dose; pruritus; rash; drug synergism; antibodies, monoclonal; cardiotoxicity; protein induction; tanespimycin; heat shock protein 90; drug clearance; hsp90 heat-shock proteins; nausea and vomiting; receptor, erbb-2; headache; heat shock protein 70; drug blood level; liver function test; phase 1 clinical trial; drug half life; drug metabolite; trastuzumab; alopecia; lymphocyte; infusions, intravenous; hypersensitivity reaction; benzoquinones; lactams, macrocyclic; kos 1297
Journal Title: Journal of Clinical Oncology
Volume: 25
Issue: 34
ISSN: 0732-183X
Publisher: American Society of Clinical Oncology  
Date Published: 2007-12-01
Start Page: 5410
End Page: 5417
Language: English
DOI: 10.1200/jco.2007.11.7960
PUBMED: 18048823
PROVIDER: scopus
DOI/URL:
Notes: --- - "Cited By (since 1996): 145" - "Export Date: 17 November 2011" - "CODEN: JCOND" - "Source: Scopus"
Altmetric Score
MSK Authors
  1. Jennifer Wheler
    11 Wheler
  2. Clifford Hudis
    840 Hudis
  3. Larry Norton
    562 Norton
  4. Neal Rosen
    359 Rosen
  5. David Solit
    431 Solit
  6. Weining Ma
    20 Ma
  7. Shanu Modi
    132 Modi