Heart and Blood Diseases

Symptoms and General Pathology

Substance Related Disorders

Wounds and Injuries

All Conditions

Cardiotoxicity

Heart Diseases

Drug-Related Side Effects and Adverse Reactions

Chemically-Induced Disorders

Radiation Injuries

Patients will have a cardiac MRI at four time points during the study

Cardiac MRI

Patients will have an echocardiogram at four time points during the study

Echocardiogram

Patients will have blood drawn at four time points to analyze micro RNAs and Biomarkers before, during and after anthracycline treatment. Patients will also have one blood draw for future genetic sequencing.

Blood Draw

Olga Salazar, MD

Early microRNAs (miRs) and Cardiac Magnetic Resonance (CMR)-derived strain analysis and detection of genes contributing to Anthracycline-Induced Cardiotoxicity (AIC) sensitivity and resistance will identify pediatric cancer patients most and least likely to develop AIC.

Plan is to enroll 110 children and adults (≥9 years old) newly diagnosed at CCMC and Nationwide Children's Hospital (55 per institution) who will receive anthracyclines as part of their chemotherapy regimen.

The duration of study participation will be approximately a year.

Patients will have a total of four study visits:

Baseline

1 week after patient's anthracycline cumulative dose hits between 60 and 100 mg/m2 After the patient has completed maximal therapy One year after completion of anthracycline treatments

Study tasks for all four visits will be:

Collection of clinical data Blood draw for micro RNA and Biomarkers Cardiac MRI Echocardiogram One time blood draw for genetics

Approaches to Identify Early Biomarkers and Pathogenesis of Anthracycline Cardiotoxicity

Integrated Basis and Translational Approaches to Identify Early Biomarkers and Pathogenesis of Anthracycline Cardiotoxicity

1. Increased myocardial T2 relaxation time in the myocardium compared to baseline as measured by T2 mapping technique

Nationwide Children's Hospital

Connecticut Children's Medical Center

Principal Investigator

Cardiomyopathies

Antineoplastic Agents

All Drugs and Chemicals

Doxorubicin

Liposomal doxorubicin

Lana J Dixon, MB BCh BAO

Anthracyclines treat up to 60% of childhood malignancies with remarkable improvements survival rates. Unfortunately anthracyclines are associated with an increased cardiomyopathy risk. One study showed an almost six-fold greater risk of developing cardiomyopathy compared to sibling controls. A retrospective pilot study showed evidence of subclinical dysfunction (including impaired global longitudinal strain) in 42/52 childhood cancer survivors. There is limited research in this area, therefore current guidelines are based on expert opinion alone and lack consensus. Current methods of detection diagnose cardiomyopathy at an irreversible stage i.e. when the compensatory mechanisms are exhausted and the left ventricular ejection fraction impaired. Small trials have shown that early treatment with standard heart failure therapy may reverse damage, further validation is however required in this cohort.

Newer techniques such as tissue doppler and strain rate imaging have shown promise for early prediction of cardiomyopathy in adult studies. Biomarkers such as troponin and NT-proBNP have also shown a correlation with cardiomyopathy.

This study (n=208) aims to use echocardiography, strain imaging, holter monitoring and MRI for early detection of cardiomyopathy. Biomarkers, both currently used (for example, troponin and NTproBNP,) and more novel (for example, IL6, MPO, and sST2) will be assessed to see if early cardiomyopathy can be predicted.

This study will explore biomarker discovery by analysing an age/gender matched subgroup for the top differentially expressed microRNA and protein biomarkers. Selected biomarkers will then be validated in a larger cohort.

CLINICAL APPOINTMENT A linked anonymised Case Report Form will be completed using participant answers and relevant aspects of their electronic care record. This will involve questions about the patient's demographics, chemotherapy history, cardiac symptoms, past medical history, medication history and family history.

Consenting patients will then have

* height, weight and blood pressure taken
* cardiovascular and respiratory examination Participants will then undergo
* SF36 quality of life questionnaire
* 6 minute walk test, grip strength
* Electrocardiogram by a trained researcher
* Venesection- 40ml blood sample from a peripheral vein by the trained researcher Crevicular fluid sample

INVESTIGATIONS

Participants will be invited for:

1. 24 hour holter monitor- arrhythmia assessment
2. Echocardiogram- diastolic and systolic function assessment, valvular analysis, global longitudinal strain
3. Magnetic resonance imaging (MRI) scan of the heart- volumetric analysis, late gadolinium enhancement and STIR imaging assessments. As part of the scan the patient will require a venflon to be inserted into a peripheral vein for gadolinium injection. A safety questionnaire will be sent to the patient prior to attendance as part of standard MRI procedure. All safety aspects will be re-assessed on the day of attendance by a trained radiographer

BLOOD SAMPLE ANALYSIS Blood samples will be sent for standard of care and cardiovascular risk assessment. Tests include a full blood picture, urea and electrolytes, C-reactive protein, iron profile, B12 and folate, lipid profile, HbA1c, NT-proBNP and high sensitivity troponin.

Additional disease associated biomarkers for example sST2, MPO, and IL6 will be quantified using immunoassays. Biomarker discovery, including transcriptomics and proteomics will be carried out to identify signatures that could predict cardiotoxicity, subclinical dysfunction, and cardiomyopathy.

Blood samples will be collected for currently used (for example troponin, NTproBNP,) and novel (for example, IL6, MPO, and sST2) biomarkers to see if we can predict early cardiomyopathy. Transcriptomics and proteomics based biomarker discovery will identify new biomarkers to allow timely diagnosis.

Late Anthracycline Induced Cardiotoxicity- Childhood Cancer Survivors

Early Detection of Late Anthracycline Induced Cardiotoxicity in Survivors of Childhood Malignancy

Number of participants with anthracycline related cardiotoxicity as defined by the British Society of Echocardiography and British Cardio-Oncology Society guidelines

Levels of high sensitivity troponin T and NT-proBNP

Queen's University, Belfast

Senior Lecturer

Neoplasms

Skin and Connective Tissue Diseases

Breast Neoplasms

Heart Failure

Other Dietary Supplements

Carnitine

Patients will be randomized to L-carnitine therapy or placebo. Patients in the treatment group will receive oral L-carnitine (3 grams daily) for 3 days prior to chemotherapy, 1 gram of intravenous L-carnitine (5 cc over 5 minutes, prior to chemotherapy) on the day of chemotherapy and oral L-carnitine (3 grams daily) for 3 days after chemotherapy.

L-carnitine

Benjamin JW Chow, MD, FRCPC

Rob S Beanlands, MD, FRCPC

Haissam Haddad, MD, FRCPC

George Wells, M.Sc., PhD

Susan Dent, MD, FRCPC

Sean Hopkins, B.Sc, RPEBC

Michele A Turek, MD, FRCPC

Breast cancer is very common and afflicts 1 in 9 North American women. The treatment of breast cancer often requires the use of chemotherapy including "anthracyclines". Anthracyclines can damage the heart resulting in heart failure and even death. Clinicians and researchers are continually seeking methods that will reduce the toxic effects of anthracycline treatment.

L-carnitine is a substance that is produced naturally in the body and is required for normal heart function. Animal studies have suggested that L-carnitine protects the heart from the effects of anthracyclines, however this has not been verified in humans.

This study will assess the potential role of L-carnitine in the prevention of anthracycline induced heart damage. The investigators will enroll 144 patients into this study. Patients will be randomly assigned to L-carnitine therapy or to standard care (no L-carnitine therapy). Patients in the L-carnitine group will receive oral and intravenous L-carnitine prior to and after their anthracycline therapy. Patients will undergo regular follow up and testing to assess heart function. The investigators believe that patients treated with L-carnitine will benefit and have fewer complications associated with anthracycline treatment.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Approaches to Identify Early Biomarkers and Pathogenesis of Anthracycline Cardiotoxicity	NCT04036045	Childhood Cance...	Cardiac MRI Echocardiogram Blood Draw	9 Years - 18 Years	Connecticut Children's Medical Center
Late Anthracycline Induced Cardiotoxicity- Childhood Cancer Survivors	NCT04852965	Anthracycline I...		18 Years -	Queen's University, Belfast
Ability of L-carnitine to Prevent Heart Damage in Breast Cancer Patients Receiving Anthracycline Chemotherapy	NCT00247975	Heart Failure	L-carnitine	18 Years -	Ottawa Heart Institute Research Corporation

Spots Global Cancer Trial Database for anthracycline induced cardiotoxicity