Phase I Study of a Third-Generation Selective Estrogen Receptor Modulator, LY353381.HCl, in Metastatic Breast Cancer

2001 ◽  
Vol 19 (7) ◽  
pp. 2002-2009 ◽  
Author(s):  
Pamela N. Münster ◽  
Aman Buzdar ◽  
Kapil Dhingra ◽  
Nathan Enas ◽  
Lan Ni ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Metastatic Breast Cancer ◽  
Phase I ◽  
Metastatic Breast ◽  
Median Number ◽  
Third Generation ◽  
Receptor Modulator ◽  
Er Positive ◽  
Dose Levels

PURPOSE: We conducted this phase I trial to determine the safety and toxicity profile of LY353381.HCl—a novel, potent, third-generation selective estrogen receptor modulator (SERM)—because this benzothiophene derivative demonstrated an SERM profile in preclinical studies. PATIENTS AND METHODS: We studied 32 patients with recurrent or metastatic breast cancer. Patients were treated in four cohorts with oral daily doses of 10, 20, 50, and 100 mg. Pharmacokinetic sampling was performed during the first 72 hours following the first dose on day 1 and during the 24 hours after the day 57 dose. Eligibility criteria included Eastern Cooperative Oncology Group performance status of 0 to 2; no significant major organ dysfunction; and at least 3 weeks elapsed since most recent hormonal therapy, chemotherapy, and estrogen replacement therapy. RESULTS: The median patient age was 56 years (range, 30 years to 76 years). The median number of prior chemotherapies for metastatic disease was one (range, zero to four), while the median number of prior hormone regimens for metastatic disease was two (range, zero to five). Receptor status was estrogen receptor (ER) positive and progesterone receptor (PR) positive, 19 patients; ER positive and PR negative, eight patients; ER positive and PR unknown, two patients; and ER and PR unknown, three patients. Dose-limiting toxicity was not observed. Treatment was well tolerated with mild to moderate hot flashes in 18 of 32 patients (56%) at all dose levels. Transvaginal ultrasound performed at baseline and after 12 weeks of treatment showed no endometrial thickening. Of the 32 patients evaluable for response, six patients had stable disease for at least 6 months with a median duration of 7.7 months (range, 6.2 months to 33.8 months). The pharmacokinetics of LY353381.HCl were generally linear with respect to time and studied dose range. CONCLUSION: As predicted in preclinical testing, daily oral LY353381.HCl is safe, is well tolerated at all tested dose levels, and may be clinically beneficial in patients with extensively pretreated metastatic breast cancer. Further studies with LY353381 to evaluate the efficacy in patients with or without prior exposure to tamoxifen and fewer overall prior regimens are under way.

Phase I/II trial of tamoxifen with or without fenretinide, an analog of vitamin A, in women with metastatic breast cancer.

1993 ◽  
Vol 11 (3) ◽  
pp. 474-477 ◽  
Author(s):  
M A Cobleigh ◽  
K Dowlatshahi ◽  
T A Deutsch ◽  
R G Mehta ◽  
R C Moon ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Vitamin A ◽  
Phase I ◽  
Mammary Cancer ◽  
Metastatic Breast ◽  
Serum Levels ◽  
Phase Iii ◽  
Antitumor Effects ◽  
Er Positive

PURPOSE Considerable attention has been focused on the chemopreventive properties of fenretinide against carcinogen-induced rodent mammary cancer. Less is known about its direct antitumor effects. The combination of tamoxifen and fenretinide is more effective than tamoxifen or fenretinide alone in prevention of rat mammary cancer. However, the combined toxicity of tamoxifen plus fenretinide in humans is unknown. Therefore, we performed a phase I/II trial in women with estrogen receptor (ER)-positive or progesterone receptor (PR)-positive, previously untreated metastatic breast cancer. PATIENTS AND METHODS Groups of three patients received tamoxifen 20 mg/d, or tamoxifen plus fenretinide 100, 200, 300, or 400 mg/d. Patients who received fenretinide enjoyed a 3-day "drug holiday" every 4 weeks. Serum levels of fenretinide and its major metabolites were monitored. Patients were monitored for known toxicities of tamoxifen and vitamin A analogs, as well as for response. RESULTS There were no significant adverse effects on renal, hepatic, hematologic, or lipid values. Nyctalopia, photophobia, cheilitis, and pruritus were not observed. Improvement or stabilization of disease occurred in 12 of 15 patients. CONCLUSION We conclude that tamoxifen administered with fenretinide is nontoxic. Phase III trials of tamoxifen versus tamoxifen plus fenretinide are warranted.

Abstract CT051: Phase I study of TTC-352 in patients with estrogen receptor-positive metastatic breast cancer

2019 ◽  
Author(s):  
Ruth M. ORegan ◽  
Randolph Hurley ◽  
Jasgit C. Sachdev ◽  
Jonathan Bleeker ◽  
Debra Tonetti ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Metastatic Breast Cancer ◽  
Phase I ◽  
Phase I Study ◽  
Metastatic Breast ◽  
Estrogen Receptor Positive

Fulvestrant in advanced breast cancer following following failure of tamoxifen and a third generation aromatase inhibitor

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 1073-1073
Author(s):  
J. Wang ◽  
S. Jain ◽  
W. Heller ◽  
D. Mackie ◽  
V. Watson ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Metastatic Breast Cancer ◽  
Advanced Breast Cancer ◽  
Aromatase Inhibitor ◽  
Endocrine Therapy ◽  
Locally Advanced ◽  
Metastatic Breast ◽  
Advanced Breast ◽  
Third Generation

1073 Background: Endocrine therapy is a key modality in the management of estrogen receptor positive metastatic breast cancer. Fulvestrant (ICI 182,780) is an estrogen receptor downregulator. It has previously been shown to be as effective as anastrozole in patients who had previously progressed on tamoxifen. Methods: A retrospective study was carried out of metastatic breast cancer patients treated at Charing Cross Hospital between 2002–2005 who had received fulvestrant following treatment failure with tamoxifen and a third generation aromatase inhibitor. All patients were postmenopausal and received fulvestrant 250mg IM every 28 days. Measurable disease was assessed by response evaluation criteria in solid tumors (RECIST). Results: A total of 45 patients were identified with a median age of 60 (range 36 to 90). The ER status was known in 95% (n=43) of patients and was positive in all cases, it was unknown in 2% (n=2). At the time of commencing fulvestrant, 96% (n=43) had metastatic disease and 4% (n=2) locally advanced disease. All patients had received at least 2 lines of prior endocrine therapy (including adjuvant therapy), at time of starting fulvestrant the median number of prior regimens was 3 (range 3–5). Fulvestrant was administered for a median of 4 months (range 1 to 20 months), with 4 patients currently still receiving therapy as of 1 November 2006. Of the 45 patients, 2.2% (n=1) achieved a partial response, while 31% (n=14) achieved stable disease for at least 6 months. Thus, 33.3% (n=15) obtained clinical benefit (defined as PR or SD for at least 6 months). The response rates based on line of therapy will be presented. Of the 45 patients, 41 were evaluable for survival data. The median survival of the remaining patients from the start of fulvestrant therapy was 9 months (range 1 to 48 months). Of the 44 patients, 14% (n=6) remain alive. The treatment was well tolerated and toxicity data will be presented. Conclusions: Fulvestrant is well tolerated and is efficacious as treatment for advanced breast cancer that has failed tamoxifen and a third generation aromatase inhibitors. No significant financial relationships to disclose.

A phase I study of BKM120, a novel oral selective phosphatidylinositol-3-kinase (PI3K) inhibitor, in combination with fulvestrant in postmenopausal women with estrogen receptor positive metastatic breast cancer.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. TPS664-TPS664 ◽  
Author(s):  
Gayathri Nagaraj ◽  
Cynthia X. Ma ◽  
Jingqin Luo ◽  
Matthew J. Ellis
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Metastatic Breast Cancer ◽  
Phase I ◽  
Postmenopausal Women ◽  
Metastatic Breast ◽  
Pi3k Pathway ◽  
Tunel Staining ◽  
Phase Ib ◽  
Estrogen Receptor Positive

TPS664 Background: PI3K pathway activation plays a crucial role in mediating endocrine therapy resistance in estrogen receptor positive (ER+) breast cancer. We have shown previously that BKM120 in combination with fulvestrant induced synergistic apoptotic cell death in long-term estrogen deprived ER+ breast cancer (LTED) cell line models, supporting the clinical investigation of this combination in ER+ breast cancer. Methods: The study is composed of the dose escalation cohort (phase IA) and the expansion cohort (phase IB). In phase IA, a standard 3+3 phase I design is employed to determine the maximum tolerated dose (MTD) of the combination of BKM120 and fulvestrant in patients (pts) with ER+ metastatic breast cancer (MBC). In phase IB, an additional 10 pts will be enrolled at the MTD to further examine the toxicity profile and preliminary efficacy of this combination. Steady state concentrations of BKM120 will be analyzed. Postmenopausal women with ER+ MBC and measurable disease per RECIST are eligible. Pts who are currently taking fulvestrant without disease progression are eligible. There is no restriction on the number of prior lines of systemic therapy for metastatic disease in phase IA but < 3 lines is required in phase IB. Treatment consists of fulvestrant 500 mg IM administered monthly on day (d) 1 of each 28-d cycle, following the loading dose of 500 mg on d1 and d15, and BKM120 orally daily on d1-28 of each cycle. The starting dose level (DL) is DL1 (Table). Correlative studies include assessing PI3K pathway abnormalities (loss of PTEN and PIK3CA mutation) on archival tumor specimen, and treatment induced inhibition of PI3K pathway activity (pAKT, pS6, Cyclin D1, subcellular localization of FOXO3a, phosphoproteomics), tumor cell proliferation (Ki67) and apoptosis (cleaved caspase 3 or TUNEL staining) on tumor biopsies collected at baseline and cycle 2 day 1 in consented patients. Enrollment to DL1 is complete and the study is currently enrolling pts to DL2. [Table: see text]

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