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.
OBJECTIVE
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.


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.


CONCLUSIONS
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.
Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA. modis@mskcc.org
Shanu
S
Modi
Alison T
AT
Stopeck
Michael S
MS
Gordon
David
D
Mendelson
David B
DB
Solit
Rochelle
R
Bagatell
Weining
W
Ma
Jennifer
J
Wheler
Neal
N
Rosen
Larry
L
Norton
Gillian F
GF
Cropp
Robert G
RG
Johnson
Alison L
AL
Hannah
Clifford A
CA
Hudis
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects* / Q000493:pharmacokinetics; D016227:Benzoquinones / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D005260:Female; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors; D006801:Humans; D007262:Infusions, Intravenous; D047029:Lactams, Macrocyclic / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D008875:Middle Aged; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis*; D000068878:Trastuzumab
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C112765:tanespimycin