Time Restricted Eating And Metformin (TEAM) in Invasive Breast Cancer (IBC) or Ductal Carcinoma in Situ (DCIS). A Randomized, Phase IIb, Window of Opportunity Presurgical Trial.
试验速览
- 阶段
- 2 期
- 状态
- 进行中（未招募）
- 入组人数
- 120
- 试验地点
- 3
- 主要终点
- Frequency of occurrence of dose limiting toxicity
研究概览
简要总结
This phase IIb trial studies the combined effect of prolonged nightly fasting and metformin hydrochloride extended release in decreasing breast tumor cell proliferation and other biomarkers of breast cancer. Preventing invasive breast cancer or DCIS. Metformin is widely used to treat type II diabetes and is associated with a decreased risk of cancer and death in diabetic individuals. Intermittent fasting may protect cancer patients from the toxic effects of chemotherapy agents without causing chronic weight loss. The combination of intermittent fasting and metformin may reduce breast cancer growth and may be used in women at risk for breast cancer or other cancers associated with being overweight.
详细描述
- Primary Interim Objective
The primary interim objective will be to assess the safety of the experimental intervention based on the frequency of occurrence of a Dose Limiting Toxicity (DLT) in the first 14 participants assigned to the experimental treatment arm. A DLT is defined as a hypoglycemic event requiring permanent discontinuation of study treatment or any grade 3 or greater adverse event (AE) possibly, probably, or definitely related to the study drug.
Hypoglycemia AEs that require permanent discontinuation of study treatment are:
- ≥ 1 grade 2 or higher neuroglycopenic symptoms and grade 2 hypoglycemia;
- occurrence ≥ 3 times of grade 2 symptoms (≥ 2 autonomic or ≥ 1 neuroglycopenic symptoms) and grade 1 or higher hypoglycemia;
- symptomatic or asymptomatic grade 3 hypoglycemia.
In the first 14 participants enrolled in the experimental arm (combination of prolonged nightly fasting and Metformin Hydrochloride Extended-Release) we can accept at most 3 participants with a DLT. If 4 or more of the first 14 participants assigned to the treatment arm experience the above-mentioned DLTs, the trial will be definitively stopped.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Prevention
- 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 with histologically confirmed luminal (ER+ve and/or progesterone [PgR]+ve >= 1%) operable IBC (cT1-2, cN0-1, Mx) candidate to elective surgery and not to neo-adjuvant treatment. Women with larger tumors who refuse neo-adjuvant chemotherapy before surgery can also be eligible. Luminal HER2+ve (cT1, cN0) IBC and DCIS are also eligible
- •Age >= 18 years
- •Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (Karnofsky >= 70%)
- •Leukocytes >= 3,000/microliter
- •Absolute neutrophil count >= 1,500/microliter
- •Platelets >= 100,000/microliter
- •Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 1.5 x institutional upper limit of normal
- •Creatinine within normal institutional limits
- •Creatinine clearance estimated with Cockcroft-Gault formula > 45 mL/min
- •Female participants of child-bearing potential must agree to use contraception such as barrier method of birth control or abstinence, prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she has to inform her study physician immediately. The effects of metformin hydrochloride extended release on the developing human fetus at the recommended therapeutic dose are unknown
- •Ability to understand and the willingness to sign a written informed consent document
排除标准
- •Body mass index (BMI) < 18.5 Kg/m^2
- •Previous treatment for breast cancer including chemotherapy and endocrine therapy within the last 12 months
- •Women who are planned to receive neoadjuvant therapy
- •Triple negative breast cancer (BC)
- •Patients with a history of cancer within the last year. NOTE: Non melanoma skin cancer is allowed.
- •Documented history of symptomatic hypoglycemia
- •Diabetic patients or participants with fasting glucose level >= 126 mg/dL
- •Known hypersensitivity or intolerance to metformin hydrochloride extended release
- •Participants should not be receiving any other investigational agents
- •Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
- •History of lactic acidosis
- •Liver dysfunction including chronic active hepatitis and cirrhosis not compensated
- •History of vitamin B12 deficiency or megaloblastic anemia
- •Chronic use of large doses of diuretics (e.g., > 80 mg furosemide)
- •Current use of oral hormonal contraceptives or female hormones in the last four weeks or 5 half-lives, excluding vaginal creams and intrauterine devices (IUDs)
- •Concomitant use of topiramate or other carbonic anhydrase inhibitors (e.g., zonisamide, acetazolamide or dichlorphenamide)
- •Pregnant or lactating women. Pregnant women are excluded from this study because even though published data from post-marketing studies have not reported a clear association between metformin hydrochloride extended release and major birth defects, miscarriage, or adverse maternal or fetal outcomes when metformin hydrochloride extended release was used during pregnancy, these studies cannot definitely establish the absence of any metformin hydrochloride extended release associated risk because of methodological limitations, including small sample size and inconsistent comparator groups. Because there is an unknown but potential risk for adverse events (AEs) in nursing infants secondary to treatment of the mother with metformin hydrochloride extended release, breastfeeding should be discontinued if the mother is treated with metformin hydrochloride extended release. Moreover, prolonged fasting is not recommended in pregnant woman
- •Women who practice any type of intermittent fasting program
- •Women who will not have anyone available to assist them in case of need
研究组 & 干预措施
Arm I (fasting, glucose monitoring, counseling, metformin)
Patients fast for >= 16 hours every night and use the continuous glucose monitoring system for 4-6 weeks. Patients also receive nutritional counseling sessions on days 0 and 10. Beginning week 2, patients also receive metformin hydrochloride extended release PO QD until the day of surgery. Treatment continues for 4-6 weeks (until surgery) in the absence of disease progression or unacceptable toxicity. Patients undergo the collection of blood samples at baseline and at the final study visit (days 28-43), and the collection of tissue at the time of surgery (days 28-43).
干预措施: Biospecimen Collection (Procedure)
Arm I (fasting, glucose monitoring, counseling, metformin)
Patients fast for >= 16 hours every night and use the continuous glucose monitoring system for 4-6 weeks. Patients also receive nutritional counseling sessions on days 0 and 10. Beginning week 2, patients also receive metformin hydrochloride extended release PO QD until the day of surgery. Treatment continues for 4-6 weeks (until surgery) in the absence of disease progression or unacceptable toxicity. Patients undergo the collection of blood samples at baseline and at the final study visit (days 28-43), and the collection of tissue at the time of surgery (days 28-43).
干预措施: Extended Release Metformin Hydrochloride (Drug)
Arm I (fasting, glucose monitoring, counseling, metformin)
Patients fast for >= 16 hours every night and use the continuous glucose monitoring system for 4-6 weeks. Patients also receive nutritional counseling sessions on days 0 and 10. Beginning week 2, patients also receive metformin hydrochloride extended release PO QD until the day of surgery. Treatment continues for 4-6 weeks (until surgery) in the absence of disease progression or unacceptable toxicity. Patients undergo the collection of blood samples at baseline and at the final study visit (days 28-43), and the collection of tissue at the time of surgery (days 28-43).
干预措施: Monitoring (Other)
Arm I (fasting, glucose monitoring, counseling, metformin)
Patients fast for >= 16 hours every night and use the continuous glucose monitoring system for 4-6 weeks. Patients also receive nutritional counseling sessions on days 0 and 10. Beginning week 2, patients also receive metformin hydrochloride extended release PO QD until the day of surgery. Treatment continues for 4-6 weeks (until surgery) in the absence of disease progression or unacceptable toxicity. Patients undergo the collection of blood samples at baseline and at the final study visit (days 28-43), and the collection of tissue at the time of surgery (days 28-43).
干预措施: Nutritional Assessment (Other)
Arm I (fasting, glucose monitoring, counseling, metformin)
Patients fast for >= 16 hours every night and use the continuous glucose monitoring system for 4-6 weeks. Patients also receive nutritional counseling sessions on days 0 and 10. Beginning week 2, patients also receive metformin hydrochloride extended release PO QD until the day of surgery. Treatment continues for 4-6 weeks (until surgery) in the absence of disease progression or unacceptable toxicity. Patients undergo the collection of blood samples at baseline and at the final study visit (days 28-43), and the collection of tissue at the time of surgery (days 28-43).
干预措施: Short-Term Fasting (Other)
Arm II (glucose monitoring)
Patients continue their usual dietary pattern and use the continuous glucose monitoring system for 4-6 weeks (until surgery). Patients undergo the collection of blood samples at baseline and at the final study visit (days 28-43), and the collection of tissue at the time of surgery (days 28-43).
干预措施: Biospecimen Collection (Procedure)
Arm II (glucose monitoring)
Patients continue their usual dietary pattern and use the continuous glucose monitoring system for 4-6 weeks (until surgery). Patients undergo the collection of blood samples at baseline and at the final study visit (days 28-43), and the collection of tissue at the time of surgery (days 28-43).
干预措施: Monitoring (Other)
结局指标
主要结局
Frequency of occurrence of dose limiting toxicity
时间窗: Up to 4-6 weeks
Defined as a hypoglycemic event requiring permanent discontinuation of study treatment or any grade 3 or greater adverse event possibly, probably, or definitely related to the study drug.
Change in pre-post treatment Ki67 labeling index in invasive breast cancer (IBC) or ductal carcinoma in situ (DCIS) (in the absence of IBC)
时间窗: Baseline up to 4-6 weeks
Generalized linear models will be used to assess differences between treatment arms for Ki67. Log transformation will be considered to obtain normal distribution of residuals. Will also evaluate the need to adjust for baseline characteristics and significant confounders (such as body mass index \[BMI\] and HER2 status).
Difference in post-treatment adjacent DCIS (in the presence of IBC), if present, or intraepithelial neoplasia Ki67 between arms
时间窗: Post-treatment (4-6 weeks)
Generalized linear models will be used to assess differences between treatment arms for Ki67. Log transformation will be considered to obtain normal distribution of residuals. Will also evaluate the need to adjust for baseline characteristics and significant confounders (such as BMI and HER2 status).
次要结局
- Change in circulating biomarkers(Baseline up to 4-6 weeks)
- Change of CIP2A-PP2A-GSK3beta-MCL-1 axis in cancer tissue(Baseline up to 4-6 weeks)
- Change of Ki67 in cancer tissue(Baseline up to 4-6 weeks)
- Difference of M30(Post-treatment)
- Difference of phosphorylated S6(Post-treatment)
- Physiological distress(Up to 4-6 weeks)
- Eating habits(Up to 4-6 weeks)
- Tobacco(Up to 4-6 weeks)
- Alcohol consumption(Up to 4-6 weeks)
- Incidence of adverse events(Up to 4-6 weeks)
- Difference of the area under the curve of glucose levels(Up to 4-6 weeks)