Aung Naing, MD

Primary Objective:

-Evaluate incidence of cardiac complications in Phase I patients.

Secondary Objective:

-To identify variables (i.e. number of electrocardiograms (EKG) performed) that lead to the detection of cardiac events.

The research plan includes a retrospective review of the chart of past UT MD Anderson Cancer Center (MDACC) patients and the experience in treating them.

All studies analyzed will be Phase I clinical trials.

Analysis is designed to collect information on the number of and timeframe within which ECGs are performed on these trials. Data on adverse events and serious adverse events, dose modifications based on ECG changes, attribution to drug, incidence and types of ECG changes specifically QTC prolongation as well as their influence on study procedures like dose limiting toxicities (DLTs) in dose escalation phase of the studies.

Study conducted using clinical records of patients treated on Phase I protocols in the MDACC Department of Investigational Cancer Therapeutics. The demographic data to be collected from patients whose charts will be analyzed will include variables such as age, gender, primary cancer, stage of the disease, performance status, treatment characteristics (i.e., number and type of prior therapies), disease status, adverse events, laboratory data (i.e., complete blood count/differential/platelets, tumor markers), and treatment outcomes.

The analysis will allow identification and descriptive analysis of the occurrence of cardiac events in the phase I population and will help define the role of protocol required EKGs in their detection.

HIPAA privacy and confidentiality guidelines will be followed. The database will be secured in the Department server. A Data coordinator has been recruited to undertake this project. The information derived from these observations will help the investigators formulate research questions and projects to develop future prospective studies.

The statistical analysis will be performed in a descriptive fashion with paired and multivariable analyses.

The analyses will be reported using summary tables, figures, and data listings. Continuous variables will be summarized using the mean, standard deviation, median, minimum, and maximum.

This study will be conducted at the MD Anderson Cancer Center in Houston, Texas.

The Role of the EKG in Anticancer Drug Development

The Role of the EKG in Anticancer Phase I Drug Development

Data review of studies, active between January 1, 2006 and December 31, 2009, who included ECGs in their safety evaluations. Use of identification and descriptive analysis of cardiac events occurrence in the phase I population to define role of protocol required EKGs in their detection. Statistical analysis performed in a descriptive fashion with paired and multivariable analyses.

M.D. Anderson Cancer Center

Olga Salazar, MD

The study is being conducted to see which cardiac tests that monitor how the heart functions during and after treatment with anthracyclines are most effective. This study will assess a new way to check the heart function of children during and after cancer treatment. Currently, doctors use echocardiograms (heart ultrasound) to see how the heart is working. Echocardiograms are currently being done as part of standard of care prior to giving anthracycline chemotherapy doses and if any cardiac problems are suspected. The new method involves Cardiac Magnetic Resonance Imagining (CMRI) and a blood tests for certain biomarkers for heart health: High sensitivity troponin, Caspase, C-reactive Protein (CRP), ventricular derived B-type natriuretic peptide (BNP), Matrix Metalloproteinases (MMPs), Tissue inhibitors of metalloproteinases (TIMPs), C terminal propeptide of type I procollagen (PICP), C terminal telopeptide of collagen type I (CITP), Troponin I, and Bone Alkaline Phosphatase. The purpose of this study is to find out if CMRI and blood tests help us to find heart problems earlier, before they are detected by echocardiograms.

This is a pilot study with a descriptive study design.

Anthracycline induced late onset cardiotoxicity, defined in terms of abnormal findings on echocardiography, has been reported to occur in 57% of childhood cancer survivors. Serial monitoring of cardiac function by means of echocardiography detects cardiac toxicity only when many of the cardiomyocytes have already been damaged. Given the lack of evidence to support the reliability of serum markers of cardiotoxicity, many recommend modifying the dose of anthracyclines only when there is objective evidence of myocardial dysfunction by echocardiograph. This approach could be responsible for the increasing frequency of dilated cardiomyopathy occurring 10-15 years after treatment. Non invasive imaging methods are thus critically needed to more precisely detect cardiotoxic changes in children receiving anthracyclines. CMRI has become the gold standard for the assessment and quantification of ventricular volumes, myocardial mass and global and regional wall function. CMRI also allows morphologic analysis of the myocardium as well as detection and characterization of pathological myocardium. In this study, the investigator therefore proposes to use serial MRI parameters in conjunction with a battery of serologic markers, obtained at intervals determined by cumulative anthracycline dose, to monitor changes in systolic function during chemotherapy and one year after the end of chemotherapy. The investigator will use a combination of a serum cardiac biomarker of inflammation (CRP), myocyte injury (Troponin, Caspases), heart failure (BNP), and extracellular matrix remodeling (PICP, CITP, Bone Alkaline Phosphatase, MMPs, TIMPs). The investigator will then correlate these findings with CMRI parameters of myocyte dysfunction. Results will be compared with standard echocardiography. The investigator predict that CMRI is a better indicator of early anthracycline cardiotoxicity in children with solid tumors and hematologic malignancies.

Patients who are of age 9 years of age or older, newly diagnosed with a malignancy that is anticipated to receive high dose anthracyclines as part of their chemotherapy (such as but not limited to solid tumors, high risk Acute Lymphocytic Leukemia, Acute Myelogenous Leukemia, and lymphomas) will be invited to participate in the study.

Specific Aim 1: To use CMRI to detect occult asymptomatic cardiotoxicity over time and in relation to cumulative dose among pediatric cancer patients treated with anthracyclines.

Specific Aim 2: To quantitate serologic biomarker profile for several functional pathways including the inflammatory cascade, MMP/TIMP remodeling pathways, signaling, cell viability and growth domains over time and in relation to cumulative dose among pediatric cancer patients treated with anthracyclines.

Specific Aim 3: To compare changes over time detected by CMRI and serologic markers of cardiac toxicity to echocardiographic indices of systolic and diastolic function and determine their ability alone or in combination to predict freedom from left ventricular dysfunction defined as change in ejection fraction at one year post chemotherapy.

These aims will test the hypothesis that CMR imaging and serologic biomarkers of inflammation, apoptosis and progressive extracellular matrix remodeling will precede echocardiographic indices of systolic and diastolic function among children receiving high dose anthracyclines as part of their chemotherapy protocol.

Study Outcome Measures

Myocardial edema in the acute phase measured by the following parameters:

* Increased myocardial mass.
* Focal areas of high signal intensity T2 weighted spin echo imaging and myocardial delayed enhancement. Significant enhancement will be defined as signal intensity increases of greater than two standard deviations above the mean value of remote normal myocardium.
* Increased myocardial T2 relaxation time in the myocardium compared to baseline as measured by T2 mapping technique
* Changes in myocardial T1 relaxation time in the myocardium pre and post-contrast compared to baseline as measured by T1 mapping technique (Modified Look-Locker inversion recovery (MOLLI). Myocardial T1 (msc).
* Decrease in myocardial strain and strain rate compared to baseline calculations: Mid wall left ventricular circumferential strain (ECC), Maximum longitudinal left ventricular strain (ELL).
* Decrease in myocardial T2\* indicative of presence of Iron in the myocardium (reflecting anthracycline-Fe complexes)(ms).
* The following markers were measured: Matrix/Fibrosis pathway:

Plasma levels of MMPs (all soluble MMP types) and TIMPs (all 4 TIMPs); Inflammatory domain: cytokines (TNFα, interleukins, interferon gamma (IFNG), TGF β2, TGF βII)),cytokine receptors (sTNF RI, sTNF RII, sSt2, sgp130, siL1-RII/sCD121b, siL-2Rα/CD25, siL-4R, siL-6R, Endoglin); Signaling pathway: growth factors (GDP-15, GCSF, VEGF, sVEGFR2 TGFβ1, IGF-1;). Changes in regional myocardial function and elevation of serologic markers may predict freedom from left ventricular dysfunction defined as ejection fraction ≥55% at 1 year.

The following tests and procedures will be done for this study:

1. CMRI tests
2. Blood tests
3. Echocardiograms

These tests noted above will be done:

1. Prior to or at before the cum dose of anthracyclines = 60 mg/m2
2. Cumulative anthracycline doses:

   * 125-175 mg/m2
   * 200-250 mg/m2
   * 275-325 mg/m2
   * After maximal anthracycline treatment
   * One year after completion of maximal anthracycline therapy

The blood tests being done are:

Matrix/Fibrosis pathway:Plasma levels of MMPs (all soluble MMP types) and TIMPs, (all 4 TIMPs); Inflammatory domain: cytokines (TNFα, interleukins, interferon gamma (IFNG), TGF β2, TGF βII)), Cytokine receptors (sTNF RI, sTNF RII, sSt2, sgp130, siL1- RII/sCD121b, siL-2Rα/CD25, siL-4R, siL-6R, Endoglin); Signaling pathway: growth factors (GDP-15, GCSF, VEGF, sVEGFR2 TGFβ1, IGF-1;

Magnetic Resonance Imaging:A Window to Anthracycline Toxicity

Myocardial edema in the acute phase measured by a composite of multiple measures that include T1 and T2 mapping, signal enhancement in T2 weighted images.

Decrease in myocardial strain and strain rate compared to baseline calculations

Elevation of serologic biomarkers CRP, Troponin, Caspases, BNP, and extracellular matrix remodeling (PCIP, CITP, PICP/CITP ratio, MMPs and MMPs/TIMP ratio

Connecticut Children's Medical Center

Director of non-invasive Cardiac Imaging, Assoc. Professor of Pediatrics

Neoplasms

Skin and Connective Tissue Diseases

All Conditions

Rare Diseases

Breast Neoplasms

Breast Diseases

Skin Diseases

Acute Graft Versus Host Disease

Breast cancer patients treated with radiotherapy

Radiotherapy

MEDIRAD-BRACE aims to determine the relationship between 3D dose distributions in cardiac structures and the risk of acute coronary events (ACE) and other cardiac complications in breast cancer (BC) patients to develop and externally validate multivariable Normal Tissue Complication Probability (NTCP) models to assess the risk of ACE in individual patients based on cardiac dose metrics in the first 10 years after BC radiotherapy.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
The Role of the EKG in Anticancer Drug Development	NCT01462383	Advanced Cancer		-	M.D. Anderson Cancer Center
Magnetic Resonance Imaging:A Window to Anthracycline Toxicity	NCT03211520	Cardiac Complic...		9 Years - 18 Years	Connecticut Children's Medical Center
Implications of MEDIcal Low Dose RADiation Exposure - BReast Cancer Acute Coronary Events	NCT03211442	Breast Cancer F... Acute Coronary ... Cardiac Complic...	Radiotherapy	40 Years - 75 Years	University Medical Center Groningen

Spots Global Cancer Trial Database for cardiac complications