Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT03211520 |
| Other study ID # |
10-066 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
February 2013 |
| Est. completion date |
June 24, 2023 |
Study information
| Verified date |
August 2023 |
| Source |
Connecticut Children's Medical Center |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational
|
Clinical Trial Summary
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.
Description:
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;
