Phase II Pre-emptive OsciLLation of ER activitY Levels Through Alternation of Estradiol/Anti-estrogen Therapies Prior to Disease Progression in ER+/HER2- Metastatic or Advanced Breast Cancer
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 19
- 试验地点
- 3
- 主要终点
- Clinical benefit
研究概览
简要总结
Before anti-estrogens such as tamoxifen were developed to treat estrogen receptor (ER)-positive breast cancer, high-dose estrogen therapies were used. This seems counterintuitive since anti-estrogens block ER function, while estrogens increase ER function, but these therapies are effective to similar extents for the treatment of metastatic ER+ breast cancer. Estrogen therapies are most effective against cancers that develop resistance to anti-estrogens, likely because such cancers have adapted to grow without ER function, and restoring ER function (with estrogen) is damaging to the cancer cells. In some patients with ER+ breast cancer that becomes resistant to anti-estrogens, treatment with the estrogen 17B-estradiol induces tumor response. Furthermore, when 17B-estradiol-sensitive tumors eventually become resistant to 17B-estradiol, switching back to anti-estrogen therapy is often effective. These observations suggest that cancers can alternate between anti-estrogen-sensitive and 17B-estradiol-sensitive states. The investigators hypothesize that treatment with alternating 17B-estradiol / anti-estrogen therapies on a defined 8-week / 16-week schedule will more effectively prevent cancer growth than continuous treatment with either type of therapy in patients with metastatic anti-estrogen-resistant ER+ breast cancer.
详细描述
Metastatic breast cancer is rarely cured by current therapies. ER+ breast cancers ultimately become resistant to all available anti-estrogens. Response rates to estrogens are similar to those of anti-estrogens in the metastatic setting. Given that ER+ breast cancers are often responsive to anti-estrogens and estrogens, alternating anti-estrogen/estrogen therapies may be more effective than continuous treatment with either type of agent. Anecdotal evidence indicates that such a strategy of alternating therapies is effective in some patients. Preclinical evidence suggests that anti-estrogen-resistant ER+ breast cancers are sensitized to the anti-tumor effects of estrogens. Such cells harbor subpopulations that can ultimately regain the ability to grow in the presence of estrogens, and revert to their anti-estrogen-sensitive state. The investigators will formally test whether alternating 17B-estradiol/anti-estrogen therapies is effective for the management of anti-estrogen-resistant metastatic ER+/HER2- breast cancer, and to identify molecular biomarkers that predict tumor response to 1) 17B-estradiol and 2) alternating 17B-estradiol/anti-estrogen therapies. If successful, this study would present a novel strategy to manage metastatic ER+/HER2- breast cancer by pre-emptively switching therapies prior to disease progression.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- Female
- 接受健康志愿者
- 否
入选标准
- •Women ≥18 years of age with clinical stage IV ER+/HER2- breast cancer, or with locally recurrent ER+/HER2- disease not amenable to therapy for curative intent.
- •Patient must have been treated with an anti-estrogen at any time in their disease history. Combination regimens that include an anti-estrogen and any biologic, or targeted therapy, are permitted (e.g., any CDK inhibitor, everolimus, or any other novel biologics), and are considered to be a single hormonal therapy based regimen.
- •Any number of prior lines of anti-estrogen (i.e., hormonal) therapy is permissible.
- •One line of prior chemotherapy for advanced/metastatic disease is permissible.
- •Histologic documentation of ER strongly+/HER2- breast cancer by core needle biopsy, fine needle aspiration, incisional biopsy, or surgical biopsy of ≥1 site(s) of metastatic or locally advanced disease performed as standard of care within the past 4 months for assessment of eligibility for study participation (except as noted below in c/d/e).
- •ER strongly+ status defined as ER staining by immunohistochemistry in ≥50% of malignant cell nuclei with an intensity ≥2+ on a scale of 0-3+. These criteria are equivalent to an Allred score ≥
- •HER2-negative status is defined as immunohistochemistry score of 0-1+, or with a FISH ratio of <2 if IHC is 2+ or if IHC has not been done (as per ASCO/CAP definitions). In cases of borderline or equivocal HER2 status, eligibility will be determined by the PI.
- •Archived tumor specimens: Excess tumor tissue must be available for research purposes. This will include tumor tissue sufficient to make ≥10 five-micron sections; more tumor tissue is preferred.
- •Freshly acquired tumor specimens: As part of a clinically indicated biopsy procedure, an additional 1-3 cores or tissue fragments will be obtained by core needle or surgical biopsy for research purposes and FFPE.
- •Patients with bone-only metastatic disease with a history of ER+/HER2- breast cancer are eligible, and bone biopsy is not required, providing their primary cancer is consistent with the above-described ER and HER2 criteria.
- •Patients with non-bone metastatic disease in whom a safe and accurate biopsy of recurrent/metastatic disease cannot be readily obtained are also eligible, providing their primary cancer is consistent with the above-described ER and HER2 criteria.
- •Patient must be a candidate for treatment with 17B-estradiol and an aromatase inhibitor.
- •If the most recent therapy was in the adjuvant setting, the recurrence-free interval (time from initiation of adjuvant anti-estrogen therapy to clinical evidence of disease recurrence) must have been ≥2 years.
- •If the most recent therapy was in the advanced/metastatic setting, the progression-free interval must have been ≥3 months (except in the case of investigational hormonal therapies).
- •Patient must be post-menopausal based on either a history of an oophorectomy, or ≥1 year of amenorrhea. An elevated serum gonadotropin level and estradiol level in the postmenopausal range (as locally defined) can be used to confirm menopausal status in a subject with <1 year of amenorrhea.
- •Baseline radiographic staging, including specifically either PET/CT, or CT (CAP) and bone scan.
- •Patient must be capable and willing to provide informed written consent for study participation.
- •The following laboratory values must be confirmed for eligibility within 28 days prior to initiation of study therapy:
- •Hematology panel
- •hemoglobin > 9 g/dL
- •white blood cell (WBC) count (≥ 2,000/uL)
- •platelet count ≥ 75,000/uL Serum biochemistry/metabolic panel
- •creatinine ≤ 1.5 x upper limits of normal (ULN)
- •total bilirubin ≤ 1.5 x upper limits of normal (ULN)
- •ALT and AST ≤ 3.0 x upper limits of normal (ULN) For patients with liver metastasis: < 5 x upper limits of normal (ULN)
排除标准
- •Treatment with fulvestrant within 16 weeks prior to study enrollment.
- •Any other concurrent systemic anti-cancer treatments, including conventional chemotherapeutic agents and biological agents, during the study period.
- •Anti-resorptive bone therapies (e.g., bisphosphonates, denosumab) are permitted.
- •Any investigational cancer therapy in the last 3 weeks.
- •Known CNS disease, unless clinically stable for ≥ 3 months.
- •History of any of the following:
- •deep venous thrombosis
- •pulmonary embolism
- •acute myocardial infarction
- •congestive heart failure
- •previous malignancy not treated with curative intent, or with an estimated recurrence risk ≥30%
研究组 & 干预措施
Alternating Therapy
Study will use an 8-week/16-week alternating regimen of 17B-estradiol/AI (aromatase inhibitor) therapy. Use of only one Aromatase inhibitor throughout the study is preferred.
17B-estradiol: One tablet containing 2 mg 17B-estradiol will be taken orally three times daily, for a total dose of 6 mg/day.
Letrozole: One tablet containing 2.5 mg letrozole will be taken orally once per day.
Anastrozole: One tablet containing 1 mg anastrozole will be taken orally once per day.
Exemestane: One tablet containing 25 mg exemestane will be taken orally once per day.
干预措施: 17B-estradiol (Drug)
Alternating Therapy
Study will use an 8-week/16-week alternating regimen of 17B-estradiol/AI (aromatase inhibitor) therapy. Use of only one Aromatase inhibitor throughout the study is preferred.
17B-estradiol: One tablet containing 2 mg 17B-estradiol will be taken orally three times daily, for a total dose of 6 mg/day.
Letrozole: One tablet containing 2.5 mg letrozole will be taken orally once per day.
Anastrozole: One tablet containing 1 mg anastrozole will be taken orally once per day.
Exemestane: One tablet containing 25 mg exemestane will be taken orally once per day.
干预措施: Letrozole (Drug)
Alternating Therapy
Study will use an 8-week/16-week alternating regimen of 17B-estradiol/AI (aromatase inhibitor) therapy. Use of only one Aromatase inhibitor throughout the study is preferred.
17B-estradiol: One tablet containing 2 mg 17B-estradiol will be taken orally three times daily, for a total dose of 6 mg/day.
Letrozole: One tablet containing 2.5 mg letrozole will be taken orally once per day.
Anastrozole: One tablet containing 1 mg anastrozole will be taken orally once per day.
Exemestane: One tablet containing 25 mg exemestane will be taken orally once per day.
干预措施: Anastrozole (Drug)
Alternating Therapy
Study will use an 8-week/16-week alternating regimen of 17B-estradiol/AI (aromatase inhibitor) therapy. Use of only one Aromatase inhibitor throughout the study is preferred.
17B-estradiol: One tablet containing 2 mg 17B-estradiol will be taken orally three times daily, for a total dose of 6 mg/day.
Letrozole: One tablet containing 2.5 mg letrozole will be taken orally once per day.
Anastrozole: One tablet containing 1 mg anastrozole will be taken orally once per day.
Exemestane: One tablet containing 25 mg exemestane will be taken orally once per day.
干预措施: Exemestane (Drug)
结局指标
主要结局
Clinical benefit
时间窗: 12 Months
Determine the rate of clinical benefit from alternating 17B-estradiol/aromatase. Clinical benefit is defined as complete response, partial response or stable disease at 24 weeks per RECIST criteria.
次要结局
- Adverse event profiles(12 Months)
- Objective response rate(8 weeks)
- Progression-free survival(12 Months)
- Predictive tumor genetic lesions(12 Months)
研究者
Mary D Chamberlin
Associate Professor of Medicine
Dartmouth-Hitchcock Medical Center