A Randomized Phase II, Double Blind Trial of Standard Chemotherapy With Metformin (vs Placebo) in Women With Metastatic Breast Cancer Receiving First to Fourth Line Chemotherapy
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 40
- 试验地点
- 5
- 主要终点
- Progression Free Survival.
研究概览
简要总结
The purpose of this study is to determine if the addition of metformin to standard chemotherapy improves progression free survival in women with metastatic breast cancer.
详细描述
A double blind Phase II randomized study of metformin versus (vs) placebo in non-diabetic women on first to fourth line chemotherapy with anthracycline, taxane, platinum, capecitabine or vinorelbine based regimens for metastatic or unresectable locally advanced breast cancer (BC). Patients were randomized to receive metformin 850 mg tablets or placebo once daily for two days as ramp-up, followed by one tablet twice a day for the duration of the study. Randomization was stratified by line of chemotherapy (1st, 2nd, 3rd and 4th line) and hormone receptor status (ER and/or PgR positive versus both negative). All patients were required to have measureable or non-measureable, but evaluable metastases at study entry. Metformin or placebo was to be continued until disease progression, even if chemotherapy was changed or stopped prior to disease progression. Recruitment took place at five sites in Ontario, Canada: Mount Sinai Hospital, Princess Margaret Cancer Centre, St. Michael's Hospital, Toronto and London Regional Cancer Centre, London.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 75 Years（Adult, Older Adult）
- 性别
- Female
- 接受健康志愿者
- 否
入选标准
- •Histologically proven invasive breast cancer with metastatic spread outside of breast, ipsilateral axillary and supraclavicular nodal areas (Histological confirmation of metastases is not required) OR, Locally advanced breast cancer that is refractory to initial anticancer treatment.
- •A decision has been made to administer single or multiple agent first or second line chemotherapy that includes one of the following agents: anthracycline, taxane, platinum, capecitabine.
- •Age: 18 to 75 years at the time of registration
- •Invasive breast cancer, any ER or PgR status
- •ECOG performance status 0-2
- •Life expectancy of at least 6 months
- •Adequate hepatic and renal function (SGOT and ALT < 1.8 X upper limit of normal for the institution, alkaline phosphatase ≤ 2X upper limit of normal for the institution, bilirubin within normal limits for the institution (expect in patients with Gilbert's syndrome who will be eligible regardless of bilirubin) and creatinine ≤ 130 umol/L)
- •Blood counts: Neutrophils must be at least 1,000/mm3 and Platelets ≥ 75,000/mm
- •Ability to understand and to provide written informed consent for the study
- •Absence of any psychological, familial, sociological, or other patient related factors that might preclude compliance with the study protocol
- •Measurable or non measurable (but evaluable) tumour must be present - radiologic or clinical evaluation must have been performed within 4 weeks prior to registration.
排除标准
- •More than one previous line(s) of chemotherapy for metastatic disease - if prior chemotherapy has been administered, the last date of treatment must have been given at least 3 weeks prior to registration [any adjuvant systemic treatment is acceptable]
- •If prior hormone therapy (as adjuvant or metastatic therapy) has been administered, it must have been stopped at least 3 weeks prior to registration
- •Radiotherapy to a target or non target lesion within 4 weeks of registration
- •Known CNS metastases
- •History of cardiac failure
- •Known hypersensitivity or allergy to metformin
- •History of or known diabetes or baseline fasting glucose ≥ 7.0 mmol/L
- •History of lactic or other metabolic acidosis
- •Use of metformin within 3 months of registration
- •Current or planned pregnancy or lactation in women of child-bearing potential. Patients of childbearing potential must have a negative serum pregnancy test.
- •Fertile patients must agree to use an effective method of contraception while on study treatment; which could include IUD, condoms or other barrier methods of birth control
- •Habitual alcohol intake of more than three drinks daily
- •Concurrent use of any biguanide medication (other than metformin as a study medication)
- •Patients with ≥ grade 2 diarrhea at baseline, malabsorption syndrome or unable to swallow oral medication
- •Previous or concurrent malignancies, except non-melanoma skin cancers, unless curatively treated and with no evidence of recurrence for ≥ 5 years.
- •Use of any investigational agent within 28 days prior to registration.
研究组 & 干预措施
Metformin
Metformin plus standard chemotherapy (containing anthracyclines, platinum, taxanes or capecitabine; first or second line).
干预措施: Metformin (Drug)
Placebo
Placebo and standard chemotherapy (containing anthracyclines, platinum, taxanes or capecitabine; first or second line).
干预措施: Placebo (Drug)
结局指标
主要结局
Progression Free Survival.
时间窗: From date of randomization to first documented progression or death, which ever occurs first, assessed up to 3 years.
Scans will be repeated every 9 weeks. Local follow up for survival will continue until all patients have died or for a maximum total follow up of 3 years, which ever occurs first. The two study arms will be compared in an intent to treat fashion using Cox proportional hazard analysis, with the stratification variables included in the model. Treatment discontinuation for toxicity or other reasons will be considered an event.
次要结局
- Change in Fasting Insulin(Baseline to Cycle 2)
- Immunohistochemical Predictors of Metformin Benefit and to Explore Changes in These Variables in Women Who Undergo Serial Biopsies of Their Metastases.(Baseline and 3 weeks.)
- Number of Participants With Grade 3 or 4 Adverse Events(Up to 30 days after end of study)
- Overall Response Rate(From baseline until time of best response, assessed up to 3 years)
- Number of Participants With Grade 1 or 2 Adverse Events(Up to 30 days after end of study)
- Change in Fasting Glucose (mmol/L)(Baseline to Cycle 2)
- EORTC Quality of Life Measures(From baseline to cycle 2 of chemotherapy)
- Gene Expression Predictors of Potential Metformin Benefit Including Exploration of Changes in These Variables in Women Who Undergo Serial Biopsies of Their Metastases(Baseline and 4 weeks)
- Change in Insulin Resistance From Baseline to Cycle 2 Measured Using Homeostatic Model Assessment (HOMA-IR)(Baseline to Cycle 2)