Health Effects After Anthracycline and Radiation Therapy (HEART): Dexrazoxane and Prevention of Anthracycline-related Cardiomyopathy

This study is currently recruiting participants.
Verified November 2013 by Children's Oncology Group
Sponsor:
Collaborators:
The Leukemia and Lymphoma Society
St. Baldrick's Foundation
Information provided by (Responsible Party):
Children's Oncology Group
ClinicalTrials.gov Identifier:
NCT01790152
First received: February 11, 2013
Last updated: November 13, 2013
Last verified: November 2013
  Purpose

We will determine echocardiographic and serum biomarkers of cardiac injury in a study of long-term pediatric T-cell leukemia and Hodgkin lymphoma survivors enrolled on 3 front-line Children's Oncology Group (COG) clinical trials (POG 9404, 9425, 9426) between 1996-2001 with certain features. Our primary aim will be to determine whether patients randomized to the experimental dexrazoxane (DRZ) arms have decreased markers of myocardial injury compared with patients treated without dexrazoxane (DRZ). This will include a one-time measurement of an echocardiographic index of pathologic left ventricular (LV) remodeling (wall thickness-dimension ratio), complemented by serum biomarkers and a physical examination for signs and symptoms of cardiomyopathy/heart failure (CHF). We will also evaluate whether DRZ's cardioprotective effect is modified by anthracycline dose, chest radiation, and selected demographic factors (age at cancer diagnosis, current age, sex).


Condition Intervention
T-cell Acute Lymphoblastic Leukemia
Intermediate Hodgkins
Advanced Hodgkins
Early Hodgkins
Other: Diagnostic/symptom checklist
Other: Anthropometry
Procedure: Echocardiogram
Procedure: Serum Biomarkers
Other: 6 minute walk test (6MWT)
Behavioral: Participant Questionnaires (ages ≥14 years only)

Study Type: Observational
Study Design: Observational Model: Case Control
Time Perspective: Prospective
Official Title: Health Effects After Anthracycline and Radiation Therapy (HEART): Dexrazoxane and Prevention of Anthracycline-related Cardiomyopathy

Resource links provided by NLM:


Further study details as provided by Children's Oncology Group:

Primary Outcome Measures:
  • Left ventricular (LV) thickness-to-dimension ratio [ Time Frame: 2 years ] [ Designated as safety issue: No ]
    A decrease in echocardiographically derived measure of pathologic left ventricle (LV) remodeling which has been shown to be an important earlier surrogate measure of subsequent heart failure in both anthracycline-exposed pediatric cancer survivors5 and in the general pediatric and adult cardiomyopathy/heart failure population. This ratio can be derived from standard measurements.


Secondary Outcome Measures:
  • Differences in serum biomarkers [ Time Frame: 2 years ] [ Designated as safety issue: No ]
    Particularly cardiac troponins and natriuretic peptides associated with acute changes following anthracycline exposure will be examined. Analyses involving markers of inflammation (hs-CRP, TNF, IL6) and more novel markers associated with heart failure in the general population (galectin-3, ST2, growth differentiation factor-15) are exploratory.

  • Quality of Life [ Time Frame: 2 years ] [ Designated as safety issue: No ]
    Based on self-report instruments will be factored into QALY estimates to answer the secondary aims.

  • Update primary disease relapse and second cancer rates [ Time Frame: 2 years ] [ Designated as safety issue: No ]
    Given additional elapsed time since last follow-up used in the prior published analyses,11-13 primary disease relapse and second cancer rates will be updated.


Biospecimen Retention:   Samples With DNA

serum


Estimated Enrollment: 420
Study Start Date: March 2013
Estimated Primary Completion Date: August 2017 (Final data collection date for primary outcome measure)
Groups/Cohorts Assigned Interventions
Stratum 1 with diagnostic interventions

Required observations are designed to be collected at one visit:

Diagnostic/symptom checklist Anthropometry Echocardiogram Serum biomarkers Troponins (cTnT, cTnI) Natriuretic peptides (BNP, NT-ProBNP) Inflammation (hs-CRP, IL-6, TNF, Galectin-3, ST2, GDF15) Fasting glucose, lipid profile, insulin, hemoglobin AIC DNA 6 minute walk test Participant Questionnaires: Quality of life, family history, physical activity, and smoking Fasting for at least 10 hours prior to the study blood draw.

Other: Diagnostic/symptom checklist
The local PI or their designee (e.g. clinician, research nurse, or clinical research associate) will be asked to complete a diagnostic and symptom checklist (see Forms Packet on COG website) related to study outcomes. A copy of the participant's most recent clinic note and current medication list also are requested.
Other: Anthropometry

Easily determined in-office physical exam parameters requested include:

  • Height
  • Weight
  • Waist circumference
  • Blood pressure (BP)
  • Heart rate
Procedure: Echocardiogram
Study participants will undergo a one-time standard 2D, M-mode, and Doppler echocardiogram per AHA/ACC task force practice guidelines at participating institutions (or their adult affiliates depending on patient age and institutional practice).
Procedure: Serum Biomarkers

All participants will have the following analytes collected under standardized conditions and processed centrally.

  • Cardiac troponins have been associated with acute anthracycline-related cardiotoxicity, and newer high-sensitivity cTnT and cTnI assays may be predictive of late-occurring LV dysfunction. Natriuretic peptides (BNP, NT-ProBNP) are produced in response to myocardial wall stress and are used to monitor CHF progression. Levels, if persistently elevated, correlate well with echocardiographic indices of myocardial dysfunction. In exploratory analyses, we will also examine the effects of selected inflammatory biomarkers.
  • Fasting lipid profile (total cholesterol, HDL, LDL, triglyceride), glucose, insulin, and hemoglobin AIC)
  • Provide optional consent to have DNA banked for future research related to analysis of possible genetic polymorphisms associated with differential risk of cardiomyopathy.
Other: 6 minute walk test (6MWT)
Ambulatory participants will be asked to undergo this simple test of functional exercise capacity. Contraindications include: 1.) history of angina or myocardial infarction within the past month, 2.) resting heart rate >120 bpm, 3.) systolic blood pressure >180 mmHg or diastolic blood pressure >100 mmHg. Any other reason for patient inability to perform this test should be documented in the respective Report Form.
Behavioral: Participant Questionnaires (ages ≥14 years only)
The time to complete questionnaires is estimated less than 45 minutes. General health status and quality of life will be assessed using the Short-Form-36. Participants also will be administered the Minnesota Living with Heart Failure questionnaire. Questionnaires will ascertain family history of cardiovascular and related diseases (e.g. diabetes). Physical activity will be assessed using questions from the Centers for Disease Control & Prevention's (CDC) Behavioral Risk Factor Surveillance System exercise & physical activity modules. Smoking history (current & lifetime) will be assessed using questions from Health and Nutritional Examination surveys.
Stratum 2 Relapse and subsequent malignancy status

Patients not eligible for Stratum 1 may still contribute data to the Secondary Aims:

Relapse and subsequent malignancy status


Detailed Description:

Given the critical role anthracyclines have in many effective cancer treatments and the risk for subsequent cardiotoxicity associated with this class of agents, development of an effective cardioprotective strategy is of great importance. Although adult studies have shown that dexrazoxane (DRZ) is effective in minimizing cardiomyopathy/heart failure (CHF) after anthracycline therapy, short and long-term data in children are much more limited. Furthermore, concerns regarding DRZ's interaction with cancer therapies and possible association with an increased risk of second cancers have limited its use among children despite possible protection against premature CHF. To address these gaps in knowledge, using a cross-sectional study design, we propose to ascertain echocardiographic and serum biomarkers of cardiac injury in a cohort of long-term pediatric T-cell leukemia and Hodgkin lymphoma survivors enrolled on 3 front-line Children's Oncology Group (COG) clinical trials (POG 9404, 9425, 9426) between 1996-2001 that featured upfront DRZ randomization and a range of anthracycline exposures commonly used in contemporary therapy (100-360 mg/m2 doxorubicin). Our primary aim will be to determine whether patients randomized to the experimental DRZ arms have decreased markers of myocardial injury compared with patients treated without DRZ. Specifically, this will include a one-time measurement of an echocardiographic index of pathologic left ventricular (LV) remodeling (wall thickness-dimension ratio), complemented by serum biomarkers and a physical examination for signs and symptoms of CHF. We will also evaluate whether DRZ's cardioprotective effect is modified by anthracycline dose, chest radiation, and selected demographic factors (age at cancer diagnosis, current age, sex). In secondary analysis, we will also update the overall- and event-free survival rates between patients on the DRZ and non-DRZ arms. Finally, we will determine whether projected quality-adjusted life years differed by randomization status, accounting for premature cardiac disease, primary disease relapse, and second cancers.

  Eligibility

Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population

Long-term pediatric T-cell leukemia and Hodgkin lymphoma survivors enrolled on 3 front-line Children's Oncology Group (COG) clinical trials (POG 9404, 9425, 9426) between 1996-2001 that featured upfront DRZ randomization and a range of anthracycline exposures commonly used in contemporary therapy (100-360 mg/m2 doxorubicin).

Criteria

Inclusion Criteria:

  • Previously enrolled and randomized on POG 9404, 9425, or 9426
  • Alive and in continuous first complete remission from their original cancer (T-cell leukemia/lymphoma [POG 9404] or Hodgkin lymphoma [POG 9425/9426])
  • Not have been diagnosed with any subsequent malignancy, with the exception of non-melanomatous skin cancer(s). Patients with history of only subsequent non-melanomatous skin cancers remain eligible.
  • All patients and/or their parents or legal guardians must sign a written informed consent (see Stratum 1 sample consent).
  • Among patients who have relapsed or have experienced a subsequent malignancy other than non-melanomatous skin cancer since their original diagnosis, the study committee will review the available data (both from COG's Statistics and Data Center (SDC) and the participating institution) to determine if individual patients are to be selected for secondary aim arm only. The study will petition the IRB specifically for a waiver of consent to include any relapse and subsequent cancer data obtained from existing records for analysis of the secondary aims. Patients selected for Stratum 2 will be those for whom late relapse or subsequent cancer is reported but who lack clear confirmation in existing records (either at SDC or at the local institution).

Exclusion Criteria:

-

  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01790152

Contacts
Contact: Eric J Chow, MD, MPH 206-667-4630 heart@fhcrc.org

Locations
United States, California
Children's Oncology Group Recruiting
Arcadia, California, United States, 91006-3776
Contact: Eric J. Chow    206-667-7724    ericchow@u.washington.edu   
Principal Investigator: Eric J. Chow         
United States, Florida
The Children's Hospital of Southwest Florida Recruiting
Fort Myers, Florida, United States, 33908
Contact: Emad K. Salman    239-343-5333      
Principal Investigator: Emad K. Salman         
All Children's Hospital Recruiting
Saint Petersburg, Florida, United States, 33701
Contact: Gregory A. Hale    727-767-2423    HamblinF@allkids.org   
Principal Investigator: Gregory A. Hale         
Saint Mary's Hospital Recruiting
West Palm Beach, Florida, United States, 33407
Contact: Narayana Gowda    888-823-5923    ctsucontact@westat.com   
Principal Investigator: Narayana Gowda         
United States, Illinois
Saint Jude Midwest Affiliate Recruiting
Peoria, Illinois, United States, 61602
Contact: Pedro A. De Alarcon    309-655-3258      
Principal Investigator: Pedro A. De Alarcon         
United States, Maryland
Johns Hopkins University Recruiting
Baltimore, Maryland, United States, 21287-8936
Contact: Kenneth J. Cohen    410-955-8804    jhcccro@jhmi.edu   
Principal Investigator: Kenneth J. Cohen         
United States, Michigan
Wayne State University Recruiting
Detroit, Michigan, United States, 48202
Contact: Zhihong J. Wang    313-576-9363      
Principal Investigator: Zhihong J. Wang         
United States, Missouri
Columbia Regional Recruiting
Columbia, Missouri, United States, 65201
Contact: Thomas W. Loew    573-882-7440      
Principal Investigator: Thomas W. Loew         
United States, New York
University of Rochester Recruiting
Rochester, New York, United States, 14642
Contact: Jeffrey R. Andolina    585-275-5830      
Principal Investigator: Jeffrey R. Andolina         
United States, North Carolina
Mission Hospitals Recruiting
Asheville, North Carolina, United States, 28801
Contact: Krystal S. Bottom    828-213-4150      
Principal Investigator: Krystal S. Bottom         
United States, Ohio
Children's Hospital Medical Center of Akron Recruiting
Akron, Ohio, United States, 44308
Contact: Steven J. Kuerbitz    330-543-3193      
Principal Investigator: Steven J. Kuerbitz         
United States, Texas
Medical City Dallas Hospital Recruiting
Dallas, Texas, United States, 75230
Contact: Carl Lenarsky    972-566-5588      
Principal Investigator: Carl Lenarsky         
Baylor College of Medicine Recruiting
Houston, Texas, United States, 77030
Contact: Karen R. Rabin    713-798-1354    burton@bcm.edu   
Principal Investigator: Karen R. Rabin         
University of Texas Health Science Center at San Antonio Recruiting
San Antonio, Texas, United States, 78229-3900
Contact: Anne-Marie R. Langevin    210-567-0653    che@uthscsa.edu   
Principal Investigator: Anne-Marie R. Langevin         
Sponsors and Collaborators
Children's Oncology Group
The Leukemia and Lymphoma Society
St. Baldrick's Foundation
Investigators
Study Chair: Eric J Chow, MD, MPH Fred Hutchinson Cancer Research Center
  More Information

No publications provided

Responsible Party: Children's Oncology Group
ClinicalTrials.gov Identifier: NCT01790152     History of Changes
Other Study ID Numbers: ALTE11C2, COG-ALTE11C2, NCI-2012-03196, U10CA095861, S0004187
Study First Received: February 11, 2013
Last Updated: November 13, 2013
Health Authority: United States: Federal Government

Keywords provided by Children's Oncology Group:
T-Cell Acute Lymphoblastic Leukemia
Hodgkins

Additional relevant MeSH terms:
Heart Diseases
Leukemia
Leukemia, Lymphoid
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Cardiomyopathies
Precursor T-Cell Lymphoblastic Leukemia-Lymphoma
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Cardiovascular Diseases

ClinicalTrials.gov processed this record on April 17, 2014