Effects of Dexrazoxane Hydrochloride on Biomarkers Associated With Cardiomyopathy and Heart Failure After Cancer Treatment

• ClinicalTrials.gov Identifier: NCT01790152
• Recruitment Status: Recruiting
• First Posted: February 13, 2013
• Last Update Posted: November 8, 2019
• Sponsor: Children's Oncology Group
• Collaborator: National Cancer Institute (NCI)
• Information provided by (Responsible Party): Children's Oncology Group

Tracking Information

• First Submitted Date: February 11, 2013
• First Posted Date: February 13, 2013
• Last Update Posted Date: November 8, 2019
• Actual Study Start Date: August 5, 2013
• Estimated Primary Completion Date: March 30, 2022 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: November 6, 2019)

• Left ventricular function and measures of pathologic remodeling (i.e., thickness-to-dimension ratio) assessed using standard 2-dimensional, M-mode, and Doppler echocardiogram [ Time Frame: Baseline ]
  Univariate tests will be used as well as examination of the entire cohort via multivariable regression adjusting for all a priori covariates of interest.
• Differences in serum biomarkers (particularly cardiac troponins and natriuretic peptides) [ Time Frame: Baseline ]
  Univariate tests will be used as well as examination of the entire cohort via multivariable regression adjusting for all a priori covariates of interest.

Original Primary Outcome Measures (submitted: February 12, 2013)

Left ventricular (LV) thickness-to-dimension ratio [ Time Frame: 2 years ]

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.

Current Secondary Outcome Measures (submitted: November 6, 2019)

• Quality of life based on self-report instruments [ Time Frame: Baseline ]
  An analytic Markov model will be created and used. Estimates and their 95% confidence will be included to explore the sensitivity of any quality-adjusted life years estimates.
• Primary disease relapse [ Time Frame: Baseline ]
  An analytic Markov model will be created and used.
• Second cancer rates [ Time Frame: Baseline ]
  An analytic Markov model will be created and used.
• Longitudinal trajectory of 2-dimensional echocardiographic parameters [ Time Frame: From time of cancer treatment to subsequent follow-up ]
  Will utilize generalized linear model-general estimation equation to model the trajectories of echocardiographic biomarker estimates (continuous outcomes) across time. Relevant model shapes will be evaluated, beginning with linear models, but also testing more flexible shapes (e.g., quadratic, cubic, or cubic spline functions with varying numbers of knots) to determine whether non-linear components are needed for fit. Will also examine interactions of dexrazoxane (DRZ) status with the selected functions of time to evaluate for differences in trajectories over time by DRZ status.

Original Secondary Outcome Measures (submitted: February 12, 2013)

• Differences in serum biomarkers [ Time Frame: 2 years ]
  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 ]
  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 ]
  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.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Effects of Dexrazoxane Hydrochloride on Biomarkers Associated With Cardiomyopathy and Heart Failure After Cancer Treatment
• Official Title: Health Effects After Anthracycline and Radiation Therapy (HEART): Dexrazoxane and Prevention of Anthracycline-Related Cardiomyopathy
• Brief Summary: This clinical trial studies the effects of dexrazoxane hydrochloride on biomarkers associated with cardiomyopathy and heart failure after cancer treatment. Studying samples of blood in the laboratory from patients receiving dexrazoxane hydrochloride may help doctors learn more about the effects of dexrazoxane hydrochloride on cells. It may also help doctors understand how well patients respond to treatment.

Detailed Description

PRIMARY OBJECTIVES:

I. To determine whether leukemia and lymphoma patients from P9404, P9425, P9426, and Dana Farber Cancer Institute (DFCI) 95-01 randomized to the experimental dexrazoxane hydrochloride (DRZ) arms have decreased markers of cardiomyopathy/heart failure (CHF) compared with patients on the standard arm.

II. To determine whether osteosarcoma patients from P9754 (all received DRZ) have decreased markers of cardiomyopathy/heart failure (CHF) compared with similarly treated osteosarcoma patients diagnosed during the same time period, but who did not receive DRZ.

III. To evaluate whether the cardioprotective effect of DRZ is modified by anthracycline (anthracycline analogue GPX-150) dose, chest radiation, and demographic factors (age at cancer diagnosis, current age, sex).

SECONDARY OBJECTIVES:

I. To determine whether leukemia and lymphoma patients from P9404, P9425, P9426, and DFCI 95-01 on the DRZ arms experienced differential rates of overall-survival and event-free survival compared with the standard therapy arms.

II. To determine whether projected quality-adjusted life years (QALY) differed by DRZ status, accounting for premature cardiac disease, primary disease relapse, and second cancers.

III. Determine the longitudinal trajectory of 2-dimensional echocardiographic parameters (focusing on left ventricular [LV] function and remodeling/geometric changes that can be reliably re-measured) among patients from time of cancer treatment through subsequent follow-up.

OUTLINE:

Patients complete a diagnostic symptom checklist, undergo a physical exam, echocardiogram, collection of serum for biomarker testing, and a 6 minute walk test, and complete quality of life, family history, physical activity, and smoking questionnaires.

• Study Type: Observational
• Study Design: Observational Model: Case-Only; Time Perspective: Prospective
• Target Follow-Up Duration: Not Provided

Biospecimen

Retention:   Samples With DNA

Description:

Serum

• Sampling Method: Non-Probability Sample
• Study Population: Patients with leukemia or lymphoma enrolled on Pediatric Oncology Group (POG) P9404, P9425, P9426, and DFCI 95-01 or osteosarcoma enrolled on P9754

Condition

• Hodgkin Lymphoma in Remission
• Leukemia in Remission
• Lymphoblastic Lymphoma
• Osteosarcoma
• Recurrent Leukemia
• Recurrent Lymphoma
• Recurrent Malignant Neoplasm

Intervention

• Other: Assessment of Therapy Complications
  Ancillary studies
• Other: Laboratory Biomarker Analysis
  Correlative studies
• Other: Quality-of-Life Assessment
  Ancillary studies
  Other Name: Quality of Life Assessment
• Other: Questionnaire Administration
  Ancillary studies

Study Groups/Cohorts

Ancillary-Correlative (laboratory biomarker analysis)

Patients complete a diagnostic symptom checklist, undergo a physical exam, echocardiogram, collection of serum for biomarker testing, and a 6 minute walk test, and complete quality of life, family history, physical activity, and smoking questionnaires.

Interventions:

• Other: Assessment of Therapy Complications
• Other: Laboratory Biomarker Analysis
• Other: Quality-of-Life Assessment
• Other: Questionnaire Administration

• Publications *: Chow EJ, Asselin BL, Schwartz CL, Doody DR, Leisenring WM, Aggarwal S, Baker KS, Bhatia S, Constine LS, Freyer DR, Lipshultz SE, Armenian SH. Late Mortality After Dexrazoxane Treatment: A Report From the Children's Oncology Group. J Clin Oncol. 2015 Aug 20;33(24):2639-45. doi: 10.1200/JCO.2014.59.4473. Epub 2015 May 26.

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: February 12, 2013): 420
• Original Estimated Enrollment: Same as current
• Study Completion Date: Not Provided
• Estimated Primary Completion Date: March 30, 2022 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• STRATUM I AND STRATUM II: LEUKEMIA AND LYMPHOMA SURVIVORS
• Previously enrolled leukemia and lymphoma survivors, randomized to + or - DRZ on P9404, P9425, P9426, or DFCI 95-01 (high-risk patients only)
• STRATUM I: Alive and in continuous first complete remission from their original cancer (leukemia/lymphoblastic lymphoma [P9404, high-risk DFCI 95-01] or Hodgkin lymphoma [P9425/P9426])
• STRATUM I: Did not have progressive disease or induction failure requiring off-protocol therapy including hematopoietic cell transplantation
• STRATUM I: Must not have been diagnosed with any subsequent malignancy that required additional cardiotoxic therapies (i.e., radiotherapy to the chest [also includes fields directed towards the neck, upper abdomen, or spine], or additional anthracyclines or anthraquinones); patients with history of subsequent malignancy that did not require such therapies remain eligible
• STRATUM I: All patients and/or their parents or legal guardians must sign a written informed consent
• STRATUM II: Among leukemia and lymphoma patients randomized to + or - DRZ on P9404, P9425, P9426, and DFCI 95-01 (high risk patients only) who have relapsed or have experienced a subsequent malignancy that precludes eligibility since their original diagnosis, the study committee will review the available data (both from Children's Oncology Group's [COG?s] Statistics and Data Center [SDC] and the participating institution) to determine if individual patients are to be selected for Stratum 2; in recognition that local institutions sometimes have more updated relapse/subsequent cancer data than SDC, in cases where local data is more updated, local data will be used preferentially; the study will petition the Institutional Review Board (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)
• STRATUM II: Alive, but have experienced relapse of their original cancer and/or have developed a subsequent cancer (other than non-melanomatous skin cancer) since their original diagnosis
• STRATUM II: All patients and/or their parents or legal guardians must sign a written informed consent
• STRATUM III: OSTEOSARCOMA SURVIVORS
• Previously enrolled osteosarcoma survivors treated on P9754 who are alive and able (themselves and/or parents/legal guardian) to provide written informed consent; note that relapse and subsequent malignancy are not exclusion criteria for P9754 survivors

• Comparison subjects for P9754 survivors will be eligible to be enrolled from any ALTE11C2 participating COG site (even if that institution did not participate on P9754), according to the following criteria:

  • Newly diagnosed, previously untreated biopsy-proven moderate or high grade osteosarcoma without metastasis; patients with low grade osteosarcoma, parosteal or periosteal sarcoma are ineligible
  • < 31 years of age at time of initial osteosarcoma diagnosis
  • Diagnosis occurred between January 1, 1999 through December 31, 2002; duration of therapy can extend beyond 2002
  • No evidence of poor or low cardiac function at time of initial osteosarcoma diagnosis; if reports from the time are available: shortening fraction >= 28% by echocardiogram and within the institutional normative range for age, or radionuclide angiogram ejection fraction >= 50%; if imaging reports from the time are no longer available, there must be no documentation within available medical records that suggest poor or low cardiac function at time of diagnosis
  • Comparison subject must have institutional records (e.g., clinic note, treatment summary, chemotherapy roadmap) documenting lifetime receipt of 450 to 600 mg/m^2 of doxorubicin (doses within 10% are acceptable); this includes initial therapy as well as any subsequent therapy for relapse or second cancer, if relevant; as such, comparison subjects who have had osteosarcoma relapse or subsequent malignancies remain eligible so long as they meet all other eligibility criteria
  • No anthracycline or anthraquinone aside from doxorubicin was ever given as part of initial or subsequent therapies
  • No exposure to DRZ at any point in time
  • All patients and/or their parents or legal guardians must sign a written informed consent
• STRATUM IV: CARDIOMYOPATHY CASES, NOT OTHERWISE ELIGIBLE FOR STRATUMS 1, 2, AND 3
• Individuals diagnosed with cancer prior to age 21 years, who required treatment with chemotherapy and/or radiotherapy, achieved initial remission, and remained alive after completing anti-cancer-therapy for at least 1 year
• Must have screening echocardiograms for heart function as part of cancer therapy and off-therapy evaluations available (Digital Imaging and Communications in Medicine [DICOM] format). Images from Video Home System (VHS) tapes and reports only (without images) are not suitable
• Cannot have a known history of congenital heart disease (patent foramen ovale remain eligible) or underlying genetic syndrome associated with abnormal cardiovascular development or health (e.g., down syndrome)
• Based on echocardiography, must have either left ventricular fractional shortening =< 28.0% or ejection fraction =< 50.0% on at least two occasions, with at least one of these measurements occurring after cancer therapy completion and be in the absence of sepsis or any uncontrolled infection
• If the fractional shortening or ejection fraction criteria is only met on one occasion, this must be after cancer therapy completion, be in the absence of sepsis or any uncontrolled infection, and the patient must have subsequently started on chronic medical therapy for cardiomyopathy (e.g., beta-blocker, angiotensin-converting enzyme [ACE]-inhibitor, angiotensin receptor blocker) lasting at least 6 months
• For all participants (stratums 1, 2, 3, and 4), all institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met

Sex/Gender

• Sexes Eligible for Study: All

• Ages: Child, Adult, Older Adult
• Accepts Healthy Volunteers: No
• Listed Location Countries: Australia, Canada, Puerto Rico, United States

Administrative Information

• NCT Number: NCT01790152
• Other Study ID Numbers: ALTE11C2; NCI-2012-03196 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ); S0004187; ALTE11C2 ( Other Identifier: Childrens Oncology Group ); COG-ALTE11C2 ( Other Identifier: DCP ); ALTE11C2 ( Other Identifier: CTEP ); R01CA211996 ( U.S. NIH Grant/Contract ); U10CA095861 ( U.S. NIH Grant/Contract ); UG1CA189955 ( U.S. NIH Grant/Contract )
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: Children's Oncology Group
• Study Sponsor: Children's Oncology Group
• Collaborators: National Cancer Institute (NCI)

Investigators

• Principal Investigator: Eric J Chow; Children's Oncology Group

• PRS Account: Children's Oncology Group
• Verification Date: July 2019