TY - JOUR
T1 - A phase I and pharmacokinetic study of TAS-108 in postmenopausal female patients with locally advanced, locally recurrent inoperable, or progressive metastatic breast cancer
AU - Blakely, L. Johnetta
AU - Buzdar, Aman
AU - Chang, Hsiu Yin
AU - Frye, Debra
AU - Theriault, Richard
AU - Valero, Vicente
AU - Rivera, Edgardo
AU - Booser, Daniel
AU - Kuritani, Jun
AU - Tsuda, Masuhiro
PY - 2004/8/15
Y1 - 2004/8/15
N2 - Purpose: TAS-108 is a novel steroidal anti-estrogen compound that has a strong binding affinity to the estrogen receptor and, in preclinical studies, has antitumor activity against tamoxifen-resistant breast cancer cell lines. The objective of this study was to investigate the safety and the pharmacokinetics in patients with previously treated advanced breast cancer. Experimental Design: TAS-108 was administered orally once daily starting at 40 mg/day, with dose escalations of 60, 80, 120, and 160 mg/day. A minimum of three patients were enrolled in each dose level, and, if no drug-related grade 3 or higher adverse events were seen in the first 14 days, the next cohort of patients was treated at the next level. Pharmacokinetic data were obtained on day 1, 2, 15, and 28 of the first course. Results: A total of 16 patients were enrolled, and most had received six to seven prior therapies. Clinical toxicities included nausea, vomiting, hot flashes, headache, weakness and fatigue; all were grade 1-2. TAS-108 had no effect on endometrial thickness based on transvaginal ultrasound evaluation. The average duration of therapy was 17.4 weeks (range, 4-60 weeks). The mean terminal half-life ranged from 8.0 to 10.7 hour in the interval of 12 to 24 hours postdose. The mean Cmax ranged from 2.8 to 21.0 ng/mL and AUC0-t from 15.1 to 148.7 ng·h/mL, this showed a linear correlation with the dose. Conclusions: TAS-108 was well tolerated in the doses studied with no maximum tolerated dose. The drug has linear pharmacokinetics, and in this heavily treated patient population, there was evidence of biological antitumor activity. A multi-institutional phase II study is planned.
AB - Purpose: TAS-108 is a novel steroidal anti-estrogen compound that has a strong binding affinity to the estrogen receptor and, in preclinical studies, has antitumor activity against tamoxifen-resistant breast cancer cell lines. The objective of this study was to investigate the safety and the pharmacokinetics in patients with previously treated advanced breast cancer. Experimental Design: TAS-108 was administered orally once daily starting at 40 mg/day, with dose escalations of 60, 80, 120, and 160 mg/day. A minimum of three patients were enrolled in each dose level, and, if no drug-related grade 3 or higher adverse events were seen in the first 14 days, the next cohort of patients was treated at the next level. Pharmacokinetic data were obtained on day 1, 2, 15, and 28 of the first course. Results: A total of 16 patients were enrolled, and most had received six to seven prior therapies. Clinical toxicities included nausea, vomiting, hot flashes, headache, weakness and fatigue; all were grade 1-2. TAS-108 had no effect on endometrial thickness based on transvaginal ultrasound evaluation. The average duration of therapy was 17.4 weeks (range, 4-60 weeks). The mean terminal half-life ranged from 8.0 to 10.7 hour in the interval of 12 to 24 hours postdose. The mean Cmax ranged from 2.8 to 21.0 ng/mL and AUC0-t from 15.1 to 148.7 ng·h/mL, this showed a linear correlation with the dose. Conclusions: TAS-108 was well tolerated in the doses studied with no maximum tolerated dose. The drug has linear pharmacokinetics, and in this heavily treated patient population, there was evidence of biological antitumor activity. A multi-institutional phase II study is planned.
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U2 - 10.1158/1078-0432.CCR-04-0321
DO - 10.1158/1078-0432.CCR-04-0321
M3 - Article
C2 - 15328180
AN - SCOPUS:4143136438
SN - 1078-0432
VL - 10
SP - 5425
EP - 5431
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 16
ER -