Phase 1b study of orteronel in postmenopausal women with hormone-receptor positive (HR+) metastatic breast cancer.
Introduction Suppressing both androgens and estrogens may circumvent hormone receptor resistance in breast cancer by reducing androgen receptor stimulation. Selective inhibition of the 17, 20-lyase enzyme by orteronel leads to decreased androgen production in men and would be anticipated to reduce estrogen and androgen production in women. Thus, we conducted a phase 1b study of orteronel in postmenopausal women with hormone-receptor positive (HR+) metastatic breast cancer. Methods The primary objective was to identify the recommended phase 2 dose (R2PD) of orteronel in women; escalation was via standard 3 + 3 design. The initial dose was 300 mg BID and escalated to 400 mg BID. Cycle length was 28 days. Enrolled patients had HR+ metastatic breast cancer and were evaluated every 8 weeks for disease progression. Results Eight heavily pre-treated women enrolled [median age: 57 yo (range 47-73)]. Four received 300 mg BID at dose level 1; 4 received 400 mg BID at dose level 2. No dose limiting toxicities (DLTs) were observed. Adverse events (AE) at least possibly related to orteronel included grade 1-2 nausea (n = 4) and bone pain (n = 3), and grade 1 hypokalemia, hot flashes, myalgia and AST elevation (n = 2). The only grade 3 AE was hypertension (n = 2) with 8 patients receiving 34 cycles of treatment. No objective responses were seen; clinical benefit was seen in 2 patients with stable disease for more than 6 months. Serum estrogens and testosterone were suppressed from baseline on both doses of orteronel. Conclusions Orteronel 400 mg BID is well tolerated in postmenopausal women, and significantly suppresses serum estrogens and testosterone. Clinical benefit was seen among heavily pretreated postmenopausal women with HR+ metastatic breast cancer.
University of Wisconsin Carbone Cancer Center, Madison, WI, USA.|Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
Murtuza
M
Rampurwala
University of Wisconsin Carbone Cancer Center, Madison, WI, USA.|Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
Kari B
KB
Wisinski
University of Wisconsin Carbone Cancer Center, Madison, WI, USA.|Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
Mark E
ME
Burkard
University of Wisconsin Carbone Cancer Center, Madison, WI, USA.|Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
Sima
S
Ehsani
University of Wisconsin Carbone Cancer Center, Madison, WI, USA.|Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
Ruth M
RM
O'Regan
Department of Biostatistics and Medical Informatics, University of Wisconsin, Madison, WI, USA.
Lakeesha
L
Carmichael
University of Wisconsin Carbone Cancer Center, Madison, WI, USA.|Department of Biostatistics and Medical Informatics, University of Wisconsin, Madison, WI, USA.
KyungMann
K
Kim
University of Wisconsin Carbone Cancer Center, Madison, WI, USA.|University of Wisconsin School of Pharmacy, Madison, WI, USA.
Jill
J
Kolesar
University of Wisconsin Carbone Cancer Center, Madison, WI, USA. at4@medicine.wisc.edu.|Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA. at4@medicine.wisc.edu.|Department of Medicine, Hematology/Oncology, University of Wisconsin, 1111 Highland Ave, WIMR Rm 6037, Madison, WI, 53705, USA. at4@medicine.wisc.edu.
Amye J
AJ
Tevaarwerk
D000368:Aged; D001943:Breast Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D005260:Female; D006728:Hormones / Q000097:blood; D006801:Humans; D007093:Imidazoles / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D008875:Middle Aged; D009281:Naphthalenes / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D017698:Postmenopause; D011960:Receptors, Estrogen / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism; D013254:Steroid 17-alpha-Hydroxylase / Q000037:antagonists & inhibitors*; D016896:Treatment Outcome
D006728:Hormones; D007093:Imidazoles; D009281:Naphthalenes; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D013254:Steroid 17-alpha-Hydroxylase; C571806:orteronel
17, 20 Lyase; Androgen receptor; Cytochrome P450 17A1; Estrogen receptor; Progesterone receptor; Steroid metabolism