Phase II Trial of Effects of the Nutritional Supplement Sulforaphane on Doxorubicin-Associated Cardiac Dysfunction (CRI18-026)
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 70
- 试验地点
- 1
- 主要终点
- Change in cardiac function after DOX therapy with or without sulforaphane through diagnostic studies
研究概览
简要总结
Cardiomyopathy is a major complication of doxorubicin (DOX) chemotherapy, and 10-21% of breast cancer patients receiving DOX experience compromised cardiac function. Recent advancements have increased cancer survivorship but it remains clinically challenging to mitigate the cardiotoxic side effects. Although there are several strategies used to reduce the occurrence and severity of DOX-induced cardiotoxicity, they are not particularly effective. Hence, there is an urgent need to develop new strategies that prevent the cardiotoxic effects of DOX but maintain its potency as a cancer therapy. Because the cellular events responsible for the antitumor activity of DOX and DOX-induced cardiotoxicity are distinctly different, it may be possible to develop therapies that selectively mitigate DOX-induced cardiotoxicity. Thus, the investigators propose to test an adjuvant therapy that combines the phytochemical sulforaphane (SFN) with DOX to attenuate DOX-induced cardiomyopathy. SFN activates the transcription factor Nrf2 and induces defense mechanisms in normal cells. Furthermore, SFN inhibits carcinogenesis and metastases and enhances cancer cell sensitivity to DOX, seemingly through Nrf2-independent mechanisms. SFN has also been tested in several clinical trials, although never together with DOX. Our early animal studies suggest that by activating Nrf2, SFN selectively protects the mouse and rat from DOX cardiotoxicity, enhances survival and enhances the effects of DOX on cancer growth in a rat breast cancer model. The investigators suspect that SFN affects DOX metabolism in cancer cells to enhance tumor regression, or it may synergistically activate other key antitumor mechanisms. Hence, SFN may improve the clinical outcome of cancer therapy by (1) attenuating DOX cardiotoxicity and (2) enhancing the effects of cancer treatment on the tumor. Our hypothesis is that SFN protects the heart from DOX-mediated cardiac injury without altering the antitumor efficacy of DOX. In Aim 1, the investigators will conduct an early-phase clinical trial to determine if SFN is safe to administer to breast cancer patients undergoing DOX chemotherapy. In Aim 2, the investigators will determine if SFN decreases DOX-induced inflammatory responses and enhances Nrf2- and SIRT1-target gene expression in breast cancer patients. Notably, transcript and protein signatures in peripheral blood mononuclear cells (PBMCs) can predict cardiac function in patients undergoing DOX chemotherapy for breast cancer. The investigators will also determine if SFN/DOX treatment activates Nrf2- and SIRT1-dependent gene expression, alters the levels of biomarkers for presymptomatic DOX-cardiotoxicity and mitigates the generation of cardiotoxic metabolites in PBMCs and plasma. These studies will facilitate the development of SFN co-treatment as a strategy to enhance the efficacy and safety of DOX cancer therapy.
详细描述
Determine whether nutritional supplement sulforaphane (SFN) is safe to administer to breast cancer patients undergoing doxorubicin (DOX) chemotherapy. The investigators have identified biomarkers for presymptomatic detection of DOX cardiotoxicity in breast cancer patients and reported that SFN alleviates DOX-induced cardiac toxicity while maintaining its anti-tumor activity in an animal model of breast cancer. SFN is in various stages of preclinical and clinical trials against different types of cancer but its safety and effects on identified markers have never been tested in patients treated with DOX. Sulforaphane is a generally recognized as a safe (GRAS) compound and this compound is currently in 61 different clinical trials including, Cystic Fibrosis, COPD, Melanoma, Breast and prostate cancer etc. (https://clinicaltrials.gov/ct2/results?term=sulforaphane\&pg=1). Avmacol Extra Strength, (Nutramax Laboratories Consumer Care, Inc. Edgewood, MD 21040) an over-the-counter dietary supplement containing broccoli seed and sprout extracts that is rich with sulforaphane, will be used in this study. This is an FDA regulated trial using an investigational drug under IND 141682. Dose considerations were made on the basis of the ongoing clinical trial "Effects of Avmacol Extra Strength® in the Oral Mucosa of Patients Following Curative Treatment for Tobacco-related Head and Neck Cancer" (https://clinicaltrials.gov/ct2/show/NCT03268993). Furthermore, Avmacol Extra Strength has never been tested as an adjuvant to try and protect the heart from DOXs harmful effects. . Therefore, the investigators are proposing to do an early-clinical trial to assess SFN safety in DOX-treated patients and possibly prevent DOX-cardiotoxicity in breast cancer patients.
Our hypothesis is that SFN protects the heart from DOX-mediated cardiac injury without affecting its antitumor efficacy. Here, the investigators will test SFN in combination with DOX-based chemotherapy for breast cancer; the investigators will assess its safety, cardio-protective properties, and anti-cancer efficacy. The investigators will also examine the effect of SFN on the expression of several biomarkers that indicate when a patient cannot tolerate DOX.1 To test our hypothesis, the investigators propose the following Specific Aims.
Aim 1: Demonstrate that co-administration of SFN protects the heart and is not associated with toxicity or reduced tumor response in breast cancer patients undergoing DOX chemotherapy.
The investigators propose a pilot clinical trial to assess the safety of SFN as a co-treatment with DOX chemotherapy. Strategy: Up to seventy breast cancer patients prescribed DOX chemotherapy will be consented then randomly assigned to receive either SFN or placebo during DOX chemotherapy. This sample size includes an additional 10 participants to allow for potential attrition. There will be a 50-50 chance of receiving SFN. The patients will be recruited from the Breast Cancer Clinic (Dr. Jones and Philipovskiy) in the Southwest Cancer Center at TTUHSC/UMC Lubbock. Cardiac function with echocardiography will be assessed and compared between arms for evidence of substantive decrease in DOX cardiotoxicity with SFN compared to placebo. Tumor size will also be compared (based on RECIST criteria) between treatment arms. The investigators will monitor treatment-emergent symptoms, hematological parameters of cancer therapy toxicity, and renal and hepatic function. Blood samples will be collected to assay markers of cardiotoxicity, including B-type natriuretic peptide and troponin.
Aim 2: Determine if SFN alters the levels of known biomarkers of DOX cardiotoxicity and affects the expression of SIRT1- and Nrf2-target genes.
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
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 18 Years 至 89 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age 18 to 89 years
- •No prior diagnosis of coronary artery, carotid artery or peripheral artery disease
- •Not pregnant or breastfeeding (urine pregnancy test will be done if female of childbearing potential)
- •Breast cancer requiring treatment with DOX-containing regimen above
- •Women in child bearing age group (18-50 years) will agree to use birth control for duration of study
- •Study subjects must be willing and able to swallow caplets, up to 8 daily.
排除标准
- •Currently on a research study with an investigational drug, or has been on one in the previous 30 days
- •Pregnant (by urine pregnancy test)
- •Baseline ejection fraction of less than 50%, evidence of left ventricular hypertrophy or baseline EKG reported as abnormal per cardiologist.
- •Inability to provide informed consent.
- •Prior history of chest radiation therapy
- •Diabetes or Hypertension or prior Myocardial infarction
- •Trastuzumab patients
- •Routinely taking vegetable or fruit-containing supplement pills (antioxidant phytochemicals) (daily vitamin pills ok)
- •Inability to follow up for safety monitoring
- •Previous or current use of cocaine or any illicit drug
- •Unable or unwilling to provide blood samples
- •Taking medications known to have cardiac effects, such as but not limited to, beta blockers, anti-arrhythmic agents, non dihydropyridine calcium channel blockers, ace inhibitors, NSAIDS, diuretic agents.
- •Unable to follow the protocol
- •Inability to receive anthracycline due to any reason (underlying baseline cardiac dysfunction due to other reasons, with an EF under 50%)
- •Patients already taking SFN OTC
研究组 & 干预措施
sulforaphane
Processed SFN-rich extract will be purchased in form of caplets from Nutramax Laboratories, Inc. 2208 Lakeside Blvd Edgewood, MD 21040. Caplets containing SFN-rich broccoli sprout extracts from Nutramax Labs will be dispensed to participants in sealed bottles with instructions to keep them in a household freezer. Size of the caplet will be about 2 cm in length. Dosing will be based on weight and will be dosed daily for 12 weeks.
干预措施: sulforaphane (Drug)
Placebo
Placebo caplets will comprise of microcrystalline cellulose from Nutramax Labs and will be dispensed to participants in sealed bottles with instructions to keep them in a household freezer. Placebo pills will be identical in appearance to the sulforaphane pills and will be dosed in a similar manner (identical number of pills based on weight, daily dosing and for 12 weeks)
干预措施: Placebo Oral Tablet (Drug)
结局指标
主要结局
Change in cardiac function after DOX therapy with or without sulforaphane through diagnostic studies
时间窗: At baseline and 1 year from baseline assessment.
2D Echo will be used to measure cardiac function amongst patients on DOX therapy who are exposed to sulforaphane or placebo.
次要结局
- Elevation of troponin levels as a surrogate evidence of DOX related cardiotoxicity will be checked at baseline, prior to each DOX therapy and then at 1 year from baseline assessment (Each cycle is 14 days).(At baseline, prior to each cycle of DOX, at completion of 4th cycle of DOX therapy and 1 year from baseline assessment.)
- Tumor size in patients on DOX therapy with or without sulforaphane treatment will be assessed at baseline, at completion of DOX chemotherapy (4 cycles planned with each cycle being 14 days) and at 1 year from baseline assessment.(2 days before first DOX treatment, 2 days after completion of 4th cycle of DOX therapy and 1 year from first DOX treatment)