Safety, activity and estrogen inhibition by exemestane in postmenopausal women with advanced breast cancer: a phase I study.
Exemestane is an irreversible, steroidal, oral aromatase inhibitor under evaluation in postmenopausal women with advanced breast cancer. A phase I study was conducted in 27 postmenopausal patients who were candidates for hormone therapy because they had advanced breast cancer and estrogen receptor-positive or unknown status. Most patients were moderately or heavily pretreated. Cohorts of at least three patients received sequentially escalating daily oral doses of 5-600 mg. The median duration of exemestane treatment was 13 weeks (range: 3-166 weeks). The maximal tolerated dose was not reached because of lack of treatment-related grade 3 or 4 toxicity. The most common adverse events, including those not related to treatment, were mild to moderate headache (44% of patients), dizziness (33%), nausea (33%), hot flushes (30%) and tumor-related pain (30%). There were three complete and four partial responses for an objective response rate of 26% (95% CI: 11.1-46.3%) in the intent-to-treat population; the median duration of response was 74 weeks (95% CI: 48-99 weeks). Exemestane, at the dose of 25 mg, maximally suppressed estradiol, estrone and estrone sulfate serum levels to 13, 5 and 10% of baseline, respectively. Exemestane appears to suppress estrogen, be well tolerated and have antitumor activity in postmenopausal women with advanced breast cancer. A large, safe therapeutic window of up to 600 mg was defined. In view of its safety and estrogen-suppression profiles, the most favorable effects were observed at the 25 mg daily dose.
Paridaens
R
R
UZ Gasthuisberg, Dienst Gezwelziekten, Leuven, Belgium.
Thomas
J
J
Wildiers
J
J
Vermeiren
P
P
Lobelle
J P
JP
di Salle
E
E
Ornati
G
G
Zurlo
M G
MG
Polli
A
A
Lanzalone
S
S
de Belder
K
K
D000328:Adult; D000368:Aged; D000730:Androstadienes / Q000009:adverse effects / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy*; D004244:Dizziness / Q000139:chemically induced; D004305:Dose-Response Relationship, Drug; D004965:Estrogen Antagonists / Q000627:therapeutic use*; D004967:Estrogens / Q000097:blood; D005260:Female; D006261:Headache / Q000139:chemically induced; D006801:Humans; D008875:Middle Aged; D009325:Nausea / Q000139:chemically induced; D017698:Postmenopause / Q000187:drug effects*
D000730:Androstadienes; D000970:Antineoplastic Agents; D004965:Estrogen Antagonists; D004967:Estrogens; C056516:exemestane