A phase I and pharmacokinetic study of TAS-108 in postmenopausal female patients with locally advanced, locally recurrent inoperable, or progressive metastatic breast cancer.
OBJECTIVE
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.


METHODS
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 trans-vaginal 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 C(max) ranged from 2.8 to 21.0 ng/mL and AUC(0-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.
Blakely
L Johnetta
LJ
Breast Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
Buzdar
Aman
A
Chang
Hsiu-Yin
HY
Frye
Debra
D
Theriault
Richard
R
Valero
Vicente
V
Rivera
Edgardo
E
Booser
Daniel
D
Kuritani
Jun
J
Tsuda
Masuhiro
M
D000284:Administration, Oral; D000368:Aged; D001943:Breast Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D004958:Estradiol / Q000031:analogs & derivatives* / Q000493:pharmacokinetics* / Q000633:toxicity*; D005260:Female; D006207:Half-Life; D006801:Humans; D008875:Middle Aged; D009362:Neoplasm Metastasis; D017698:Postmenopause; D016019:Survival Analysis
C482068:TS 108; D004958:Estradiol