Evaluation of Possible Safety and Efficacy of Fenofibrate in the Prophylaxis of Doxorubicin Induced Cardiotoxicity in Breast Cancer Patients
Study Details
Study Description
Brief Summary
This study aims at evaluating the possible safety and efficacy of fenofibrate in attenuating doxorubicin related cardiac toxicity in breast cancer patients.
Condition or Disease | Intervention/Treatment | Phase |
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Phase 4 |
Detailed Description
Breast cancer represents the most frequently diagnosed malignancy and the second most common cause of cancer death worldwide (Sung et al., 2021). In Egypt, breast cancer is the most common malignancy in women, accounting for 38.8% of cancers in this population, with the estimated number of breast cancer cases nearly 22,700 in 2020 and forecasted to be approximately 46,000 in 2050 (Ibrahim et al., 2014).
Doxorubicin (DOX) is a cytotoxic agent that is commonly used for treatment of breast cancer. Despite its effectiveness, doxorubicin is associated with cumulative and potential cardiotoxicity (Rawat et al.,2021).
Although the precise mechanisms whereby DOX induces myocardial injury have not been fully elucidated, it is widely accepted that DOX induces cardiac injury via several mechanisms, including activation of nuclear factor- Kabba B (NF-ĸB), the induction of pro-inflammatory cytokines, the generation of free radicals, the promotion of apoptotic cell death, and the suppression of Endothelial progenitor cells (EPC) mobilization and function, which are typical changes observed in DOX-induced cardiotoxcity (Cardinale et al., 2020).
Peroxisome proliferator-activated receptor-α (PPARα) has been proposed as a key lipid metabolism modulator and regulator of inflammation. There are three isotypes of PPAR (α, β and ȣ) which have distinct but overlapping functions. Fenofibrate, an important PPAR- α agonist, is widely used in in the treatment for hypercholesterolemia and hypertriglyceridemia (Kim and Kim, 2020). Many studies demonstrated the pleiotropic effects of fenofibrate on the heart that afford direct myocardial protection in addition to the lipid-lowering effects through improvement of vascular endothelial function, reducing oxidative stress and increasing endothelial nitric oxide synthase (eNOS) activation (Walker et al., 2012; Jen et al., 2016).
In addition recent animal study showed that fenofibrate decreased the transactivation of Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), activated endothelial nitric oxide synthase (eNOS) and increased nitric oxide (NO) bioavailability, which in turn suppressed MMP-2 (matrix 4 metalloproteinase-2) and MMP-9 (matrix metalloproteinase-9), a well-recognized mediator of adverse ventricular fibrosis and subsequent remodeling, which established the role of fenofibrate against DOX-induced cardiotoxicity in mice (Huang et al., 2021). In addition, it is known that DOX- increases circulating N-terminal pro-B-type natriuretic peptide (NT- pro-BNP) and B-type natriuretic peptide (BNP) that were attenuated by fenofibrate (Huang et al., 2021)
Study Design
Arms and Interventions
Arm | Intervention/Treatment |
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Placebo Comparator: Placebo group 22 patients which will receive four cycles of AC regimen (doxorubicin and cyclophosphamide; each cycle is given every 21 day) plus placebo tablets once daily. |
Other: Placebo
Placebo is made to look exactly like a real drug but is made of an inactive substance.
Drug: Doxorubicin
Anthracycline derived chemotherapy used in treatment of breast cancer
Drug: Cyclophosphamide
Alkylating agent used in treatment of breast cancer
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Active Comparator: Fenofibrate group 22 patients which will receive four cycles of AC regimen (doxorubicin and cyclophosphamide; each cycle is given every 21 day) plus Fenofibrate 160 mg once daily. |
Drug: Fenofibrate
It is an approved drug for hypercholesterolemia, It lowers lipid levels by activating peroxisome proliferator-activated receptor alpha (PPARα).
Drug: Doxorubicin
Anthracycline derived chemotherapy used in treatment of breast cancer
Drug: Cyclophosphamide
Alkylating agent used in treatment of breast cancer
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Outcome Measures
Primary Outcome Measures
- Assessment of changes in ejection fraction (the amount of blood that heart pumps each beat) using echocardiography [3 months]
The primary outcome is to avoid decrease in patients ejection fraction while administrating doxorubicin which is known to cause a declination in cardiac ejection fraction threatening of heart failure
Secondary Outcome Measures
- Changes in serum levels of the measured biological markers [3 months]
The secondary outcome is decrease in serum levels of the measured biological markers which are brain naturetic peptide and myeloperoxidase
Eligibility Criteria
Criteria
Inclusion Criteria:
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Age ≥ 18 years old.
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Patients with biopsy confirmed diagnosis breast cancer and with stage II and stage III breast cancer according to the American Joint Committee on Cancer (TNM staging system of breast cancer).
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Patients with performance status <2 according to Eastern Cooperative Oncology Group (ECOG) score.
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Adequate baseline hematologic values (absolute neutrophilic count ≥ 1.5 × 109/L, platelet count ≥ 100 × 109/L and hemoglobin level ≥ 10 g/dl).
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Patients with adequate liver function (serum bilirubin < 1.2 mg/dl) and adequate renal function (serum creatinine < 1.5 mg/d).
Exclusion Criteria:
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Patients with prior exposure to anthracyclines in the last 6 months.
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Patients with evidence of metastasis at the initial assessment.
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Concomitant use of antioxidant vitamins (vitamin A, C, E).
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Presence of clinical evidence for severe cardiac illness (angina pectoris, uncontrolled hypertension, arrhythmias and left ventricular ejection fraction <50%).
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Patients with inflammatory diseases (ulcerative colitis, rheumatoid arthritis).
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Patients with conditions associated with oxidative stress (smoking, tuberculosis, comorbid obesity).
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Patients who are candidates for monoclonal antibodies such as Trastuzumab and other targeted therapy (HER2 positive patients).
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Patients with active liver disease (cirrhosis, fatty liver, hepatitis C, etc..).
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Patients with myopathy.
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Patients with renal impairment, including those with end-stage renal disease and those receiving dialysis.
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Pregnant and breast feeding women.
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Known allergy to the fenofibrates.
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Concurrent use of statin, colchicine, ciprofibrate, idelalisib, ivacaftor, aspirin low strength, clopidogrel, warfarin, enzyme inducers (phenytoin, phenobarbitone, carbamazepine,…), enzyme inhibitors (allopurinol, MAOI, SSRI,…), drugs with high plasma protein binding capacity (sulfonamides, valproate, oral hypoglycemic, warfarin,…) in order to avoid potential pharmacodynamics and pharmacokinetic drug interactions.
Contacts and Locations
Locations
No locations specified.Sponsors and Collaborators
- Tanta University
Investigators
- Principal Investigator: Hagar Dewidar, Instructor, Faculty of pharmacy - Tanta university
Study Documents (Full-Text)
None provided.More Information
Publications
- Amin MB, Greene FL, Edge SB, Compton CC, Gershenwald JE, Brookland RK, Meyer L, Gress DM, Byrd DR, Winchester DP. The Eighth Edition AJCC Cancer Staging Manual: Continuing to build a bridge from a population-based to a more "personalized" approach to cancer staging. CA Cancer J Clin. 2017 Mar;67(2):93-99. doi: 10.3322/caac.21388. Epub 2017 Jan 17.
- Cardinale D, Iacopo F, Cipolla CM. Cardiotoxicity of Anthracyclines. Front Cardiovasc Med. 2020 Mar 18;7:26. doi: 10.3389/fcvm.2020.00026. eCollection 2020.
- Czupryniak L, Joshi SR, Gogtay JA, Lopez M. Effect of micronized fenofibrate on microvascular complications of type 2 diabetes: a systematic review. Expert Opin Pharmacother. 2016 Aug;17(11):1463-73. doi: 10.1080/14656566.2016.1195811. Epub 2016 Jun 15.
- Huang WP, Yin WH, Chen JS, Huang PH, Chen JW, Lin SJ. Fenofibrate attenuates doxorubicin-induced cardiac dysfunction in mice via activating the eNOS/EPC pathway. Sci Rep. 2021 Jan 13;11(1):1159. doi: 10.1038/s41598-021-80984-4.
- Ibrahim AS, Khaled HM, Mikhail NN, Baraka H, Kamel H. Cancer incidence in egypt: results of the national population-based cancer registry program. J Cancer Epidemiol. 2014;2014:437971. doi: 10.1155/2014/437971. Epub 2014 Sep 21.
- Jen HL, Liu PL, Chen YH, Yin WH, Chen JW, Lin SJ. Peroxisome Proliferator-Activated Receptor alpha Reduces Endothelin-1-Caused Cardiomyocyte Hypertrophy by Inhibiting Nuclear Factor-kappaB and Adiponectin. Mediators Inflamm. 2016;2016:5609121. doi: 10.1155/2016/5609121. Epub 2016 Oct 11.
- Kim NH, Kim SG. Fibrates Revisited: Potential Role in Cardiovascular Risk Reduction. Diabetes Metab J. 2020 Apr;44(2):213-221. doi: 10.4093/dmj.2020.0001.
- Rawat PS, Jaiswal A, Khurana A, Bhatti JS, Navik U. Doxorubicin-induced cardiotoxicity: An update on the molecular mechanism and novel therapeutic strategies for effective management. Biomed Pharmacother. 2021 Jul;139:111708. doi: 10.1016/j.biopha.2021.111708. Epub 2021 May 13.
- Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021 May;71(3):209-249. doi: 10.3322/caac.21660. Epub 2021 Feb 4.
- Walker AE, Kaplon RE, Lucking SM, Russell-Nowlan MJ, Eckel RH, Seals DR. Fenofibrate improves vascular endothelial function by reducing oxidative stress while increasing endothelial nitric oxide synthase in healthy normolipidemic older adults. Hypertension. 2012 Dec;60(6):1517-23. doi: 10.1161/HYPERTENSIONAHA.112.203661. Epub 2012 Oct 29.
- Breast cancer and fenofibrate