A Phase II Study of Metformin in Combination With Doxycycline in Patients With Localized Breast, and Uterine, and Cervical Cancer
试验速览
- 阶段
- 2 期
- 状态
- 终止
- 入组人数
- 29
- 试验地点
- 2
- 主要终点
- Change in the percent of stromal cells expressing Caveolin-1 (CAV1) at an intensity of 1+ or greater assessed by immunohistochemistry
研究概览
简要总结
This phase II trial studies how well metformin hydrochloride works together with doxycycline in treating patients with localized breast or uterine cancer. Metformin hydrochloride may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Doxycycline may stop the growth of bacteria by keeping them from making proteins and minimized the toxic side effects of anti-cancer therapy. It is not yet known whether giving metformin hydrochloride together with doxycycline may be a better way in treating patients with localized breast or uterine cancer.
详细描述
PRIMARY OBJECTIVES:
I. To determine if treatment with a combination of metformin and doxycycline can increase the percentage of cells that express Caveolin-1 in the cancer associated fibroblasts of patients with breast, or uterine, and cervical cancers.
SECONDARY OBJECTIVES:
I. To determine the effect of metformin and doxycycline treatment on the percentage of cells that express monocarboxylate transporter (MCT)4 in cancer associated fibroblasts and MCT1 and transporter of outer mitochondrial membrane (TOMM)20 in the cancer cells of breast and uterine cancer patients.
II. To assess safety and tolerability of metformin and doxycycline treatment in subjects with breast and uterine cancer.
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
- •In order to be eligible for participation in this trial, the subject must:
- •Diagnosis of localized breast or uterine cancer that is either biopsy proven or suspected based on history, physical, and or radiographic findings, and who are planned for definitive resection of the tumor without the use of neoadjuvant chemotherapy or radiation therapy at TJUH are eligible to participate.
- •Subjects must be ≥ 18 years of age at time of consent.
- •Subjects must be newly diagnosed or suspected to have breast, uterine (endometrial cancer with histologies including endometrioid, serous, clear cell, and carcinosarcoma) or cervical cancer.
- •Patient must be able to swallow pills.
- •Patients with serum creatinine levels less than 1.5 mg/dL.
- •Women of child bearing potential must have a negative urine or blood pregnancy test within 14 days of study enrollment.
- •Informed Consent: All subjects must be able to comprehend and sign a written informed consent document.
- •ECOG Performance status <1
排除标准
- •The subject must be excluded from participating in the trial if the subject:
- •Received any prior cancer therapy for the breast or uterine cancer that is being resected, including progesterone therapy for endometrial cancer patients.
- •a. Patients may have had prior therapy for other contra-lateral breast cancer.
- •Subjects who are pregnant or breastfeeding or may become pregnant during metformin and doxycycline administration.
- •Subjects on metformin or doxycycline for any reason during the preceding 4 weeks.
- •Diabetic subjects that are managed by taking metformin or insulin.
- •Subjects who have received iodinated contrast dye must wait 12 hours prior to starting Metformin. If a CT scan with contrast is scheduled after screening and consent, the metformin cannot be taken until after the CT with contrast has been completed and they have waited 12 hours.
- •Patients with serum creatinine level greater than 1.5 mg/dL.
- •Patients with history of lactic or any other metabolic acidosis.
- •Patients with history of congestive heart failure stage III or greater.
- •Patients scheduled for definitive cancer surgical resection less than 7 days from beginning of study drug administration or greater than 6 weeks from beginning study drug administration.
- •Patients with history of hepatic dysfunction or hepatic disease and abnormal liver function tests defined as AST, ALT, Alk Phos, and or total bilirubin greater than 2.5 times the upper limit of normal.
- •a. Patients who have a history of hepatic dysfunction or hepatic disease and normal liver function tests will be eligible to participate.
- •Patients with a current history (in the past 30 days) of heavy drinking which is defined in accordance with CDC definition as more than 8 drinks per week for women and more than 15 drinks per week for men. A standard drink contains .6 ounces of pure alcohol. Generally, this amount of pure alcohol is found in 12-ounces of beer, 8-ounces of malt liquor, 5-ounces of wine, 1.5-ounces or a "shot" of 80-proof distilled spirits or liquor (e.g., gin, rum, vodka, or whiskey). While on study, patients should limit their alcohol consumption to no more than 8 drinks per week for women and no more than 15 drinks per week for men. Patients who feel they cannot comply with this recommendation are not eligible.
- •Prior allergic reaction to metformin, doxycycline, or any other tetracycline antibiotic in the past.
- •Patient is on medications that are contraindicated with metformin or doxycycline under current FDA recommendations. The following is a list of medications identified as class D (consider therapy modification) when treatment with metformin or doxycycline is considered:
- •Bismuth Subsalicylate
- •Cimetidine
- •Iodinated contrast agents
- •Somatropin
研究组 & 干预措施
Treatment (metformin hydrochloride, doxycycline)
Patients receive metformin hydrochloride orally daily on days 1-3 and twice a day starting on day 4. Patients also receive doxycycline orally every 12 hours starting on day 1. Treatment repeats every 7 days for up to 2 courses in the absence of disease progression or unacceptable toxicity.
干预措施: Metformin Hydrochloride (Drug)
Treatment (metformin hydrochloride, doxycycline)
Patients receive metformin hydrochloride orally daily on days 1-3 and twice a day starting on day 4. Patients also receive doxycycline orally every 12 hours starting on day 1. Treatment repeats every 7 days for up to 2 courses in the absence of disease progression or unacceptable toxicity.
干预措施: Doxycycline (Drug)
结局指标
主要结局
Change in the percent of stromal cells expressing Caveolin-1 (CAV1) at an intensity of 1+ or greater assessed by immunohistochemistry
时间窗: Baseline to week 6
Within-patient change in immunohistochemistry scores will be analyzed using the Wilcoxon signed-rank test.
Change in the Percentage of Stromal Cells Expressing Caveolin-1 (CAV1) at an Intensity of 1+ or Greater by Immunohistochemistry
时间窗: Pre-treatment (Baseline) and Post-treatment (week 6)
Caveolin-1 (CAV1) expression in stromal cells is assessed by immunohistochemistry using a standard intensity scale of 0 to 3+, where 0 indicates no staining and 1+, 2+, and 3+ indicate increasing levels of staining intensity. For this measure, stromal cells with CAV1 staining of 1+ or higher are considered positive. Results are reported as the percentage of positive stromal cells, ranging from 0% (no positive cells) to 100% (all cells positive). Higher percentages indicate a worse outcome, as higher CAV1 expression is associated with more aggressive tumor behavior. Within-patient changes will be analyzed using the Wilcoxon signed-rank test.
次要结局
- Incidence of adverse events evaluated using National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0(At 30 days after last dose of metformin and doxycycline)
- Change in the percent of stromal cells expressing express Monocarboxylate Transporter 4 (MCT4) in the cancer cells(Baseline up to week 5)
- Change in the percent of tumor cells that express Monocarboxylate Transporter 1 (MCT1) and Transporter of Outer Mitochondrial Membrane 20 (TOMM20) in the cancer cells(Baseline up to week 5)
- Percentage of stromal cells expressing Caveolin-1 (CAV1) or Monocarboxylate Transporter 4 (MCT4)(Baseline up to week 5)
- Percentage of tumor cells that express Monocarboxylate Transporter 1 (MCT1) and Transporter of Outer Mitochondrial Membrane 20 (TOMM20)(Baseline up to week 5)
- Progress-free survival(Up to 12 months post last dose of metformin and doxycycline)
- Overall survival(Up to 12 months post last dose of metformin and doxycycline)
- Objective response rate(Up to 12 months post last dose of metformin and doxycycline)
- Number of Adverse Events(12 months)
- Change in the Percent of Stromal Cells Expressing Express Monocarboxylate Transporter 4 (MCT4) in the Cancer Cells(at 5 weeks)
- Percent of Tumor Cells That Express Transporter of Outer Mitochondrial Membrane 20 (TOMM20) in the Cancer Cells(at 5 weeks)
- Percentage of Stromal Cells Expressing Caveolin-1 (CAV1) or Monocarboxylate Transporter 4 (MCT4)(5 weeks)
- Percentage of Tumor Cells That Express Monocarboxylate Transporter 1 (MCT1)(Pre-treatment (Baseline) and Post-treatment (week 6))
- Progression-free Survival(1 year)
- Overall Survival (OS)(12 months)
- Clinical Response Rate(12 months)