Pilot Study of an NTproBNP Guided Strategy of Cardioprotection (NTproBNP-Guide)

A Randomized, Open Label Pilot Trial of a Biomarker Guided Strategy of Cardioprotection in Patients With Lymphoma or Breast Cancer Treated With Anthracyclines

Investigators will evaluate the safety and feasibility of a biomarker-guided cardioprotection strategy using NTproBNP, as compared to usual care, in breast cancer and lymphoma patients treated with anthracyclines.

Study Overview

• Status: Completed
• Conditions: Heart Failure; Lymphoma; Breast Cancer; Cardiomyopathies; Cardiotoxicity; Toxicity Due to Chemotherapy
• Intervention / Treatment: Other: Biomarker Guided Intervention

Detailed Description

This is a randomized, open-label pilot trial of a biomarker-guided strategy using NT-proBNP to identify and treat patients with a high risk of cancer therapy-related cardiotoxicity. Patients will be enrolled and randomized prior to initiation of anthracycline-based therapy and followed for 12 months with blood samples, echocardiography, and patient reported outcomes surveys. The overall hypothesis is that a biomarker guided treatment strategy that initiates neurohormonal antagonists in breast cancer or lymphoma patients who have increases in NT-proBNP prior to, during, or after anthracyclines will be feasible, well-tolerated, and result in attenuation of cardiotoxicity, compared to standard care.

• Study Type: Interventional
• Enrollment (Actual): 108
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Duarte, California, United States, 91010
      • City of Hope
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Abramson Cancer Center at University of Pennsylvania
    • West Chester, Pennsylvania, United States, 19380
      • Chester County Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Provision of written informed consent and HIPAA authorization
• Stated willingness to comply with all study procedures and availability for the duration of the study
• Male or female, ≥ 18 years of age
• Diagnosed with breast cancer or lymphoma (any subtype), planned to receive an anthracycline based chemotherapy regimen. Patients may be enrolled up to their first dose of anthracycline even if they have already received other chemotherapeutic or targeted agents as part of neo-adjuvant or adjuvant systemic therapy.

Exclusion Criteria:

• Diagnosed with Stage IV breast cancer
• Uncontrolled blood pressure defined by Systolic Blood Pressure (SBP) > 180mmHg on two or more occasions and taking three or more antihypertensives within 1 month prior to enrollment.
• Baseline SBP < 90mmHg within 1 month prior to enrollment (if multiple blood pressures are available in the medical record within 1 month prior to enrollment, the average SBP will be considered)
• Women must not be pregnant or breast-feeding due to the potential harm to an unborn fetus and possible risk for adverse events in nursing infants with some anti-hypertensives, including angiotensin receptor blockers. All females of childbearing potential must have a blood test or urine study within 10 days prior to enrollment to rule out pregnancy. All females of childbearing potential must be strongly advised to use accepted and effective methods of contraception or to abstain from sexual intercourse for the duration of their participation in the study. A female of childbearing potential is defined as any woman, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1) has achieved menarche at some point, 2) has not undergone a hysterectomy or bilateral oophorectomy; or 3) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months).
• Patient with prior or concurrent malignancy whose natural history of treatment, in the opinion of the investigator, has the potential to interfere with the safety or efficacy assessment of the investigational regimen
• Patient must not have any of the following
• Severe hepatic impairment, defined as serum bilirubin > Upper Limit of Normal (ULN), or AST or ALT > 5.0 ULN on most recent labs prior to enrollment. Results of serum bilirubin, AST, and ALT must be checked for screening if no results available in the medical recordwithin 28 days prior to enrollment.
• end-stage renal failure on dialysis
• hyperkalemia with a potassium > 5.5 mEq/l on most recent labs prior to enrollment. Serum potassium must be checked for screening if no results available in the EMR within 28 days prior to enrollment.
• a history of kidney transplant
• an eGFR < 30 ml/min/1.73m2 at most recent check prior to enrollment. Creatinine must be checked for screening if no results available in the EMR within 28 days prior to enrollment
• cardiogenic shock
• decompensated heart failure requiring the use of IV inotropic therapy
• Non-English speaking

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Biomarker Guided Arm; NTproBNP will be monitored serially prior to start of anthracycline based chemotherapy, at each cycle of anthracycline based chemotherapy, and at 3 month intervals for a total of 12 months. Clinical, echocardiographic, and biomarker data will be collected on all patients at baseline and at standardized intervals at 3, 6, 9, and 12 months following initiation of Anthracycline chemotherapy.	Other: Biomarker Guided Intervention; NTproBNP above the upper limit of normal will trigger the initiation of heart failure therapy with counseling from a study investigator based on protocol specified algorithm.
No Intervention: Usual Care; NTproBNP will not be monitored while patients are on study unless clinically indicated. Clinical, echocardiographic, and biomarker data will be collected on all patients at baseline and at standardized intervals at 3, 6, 9, and 12 months following initiation of Anthracycline chemotherapy. Biomarker data will also be collected at each cycle of Anthracycline chemotherapy.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Recruitment Rate	percent of patients approached about the study who provided consent	At baseline
Retention Rate	percent of randomized patients who complete the study per protocol	Through study completion (expected to be 1 year)
Compliance Rate	Compliance by Patient Reported Outcomes Information System (PROMIS) Scale v1.0 for patients in the biomarker guided arm initiated on heart failure medications. A higher PROMIS compliance score indicates better compliance with medications (score ranges from 9 - 45).	Through study completion (expected to be 1 year)
Maximum Dose	Maximum dose (mg) of neurohormonal antagonist therapy for participants in the intervention arm who initiated neurohormonal therapy for NTproBNP elevation across all study timepoints. Please note, due to numeric validation requirement, the max dose for combination drugs reported below is the max dose for the component in our algorithm (e.g. valsartan-hydrochlorothiazide is reported below as 325, which is the max dose of valsartan).	Through study completion (expected to be 1 year)
Incidence of Adverse Events	Number of patients that had at least one targeted AE of grade 3 or higher at any time on study.	12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in NTproBNP	Change in estimated core lab measured NTproBNP by group. GEE model adjusted for baseline values and time since anthracycline initiation, modeled with spline function. NTproBNP is a hormone released when the heart is under stress. Concentrations greater than 125 pg/ml are considered to be elevated.	Through study completion (1 year)
Change in Left Ventricular Ejection Fraction (LVEF)	Change in core-lab quantitated LVEF by echocardiogram from baseline. GEE model adjusted for baseline values and time since anthracycline initiation, modeled with spline function. LVEF is a measurement of how much blood the heart pumps out with each beat. It is calculated by dividing the volume of blood ejected with each beat divided the volume of blood in the heart, multiplied by 100 and reported as a percentage. An LVEF of less than 50% is considered abnormal.	12 months
Incidence of Cardiotoxicity	Incidence of cardiotoxicity defined as LVEF decline of at least 10% to less than 50%	12 months
Incidence of Heart Failure (HF)	Incidence of new or worsened clinical heart failure, defined as urgent or new office or emergency department visit or hospitalization for adjudicated heart failure.	12 months
Frequency of Cancer Treatment Interruptions	Frequency of cancer treatment interruptions (holds or early discontinuations)	Through study completion (expected to be 1 year)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Diastolic Function on Echo	GEE model of change in core lab measured E/e'. E/e' is a measure of diastolic function derived from the ratio of the pulse wave Doppler interrogations of the mitral inflow at the mitral valve leaflet tips and at the lateral and septal mitral annulus via tissue Doppler imaging. This measure provided insight into myocardial relaxation, preload, and left ventricular filling pressures, with values > 14 indicative of elevated filling pressure. GEE model is adjusted for baseline values and time since anthracycline initiation, modeled with spline function.	12 months
Change in Longitudinal Strain	Change in core-lab quantitated estimated global longitudinal strain by echocardiogram. GEE model adjusted for baseline values and time since anthracycline initiation, modeled with spline function. Global longitudinal strain (GLS, %) averaged from 3 apical views (left ventricular apical 4-chamber, 2-chamber, and 3-chamber) was obtained using speckle-tracking technology using Tomtec Imaging Systems. GLS is a more sensitive measure of cardiac function, with values greater than -16% (e.g., -15%) for GLS associated with worse outcomes.	12 months
Change in Circumferential Strain	Change in core-lab measured circumferential strain by echocardiogram. GEE model adjusted for baseline values and time since anthracycline initiation, modeled with spline function. Circumferential strain (%) from the short axis view (mid left ventricle) was obtained using speckle-tracking technology using Tomtec Imaging Systems. Circumferential strain is a more sensitive measure of cardiac function, with values or greater than -20% (e.g., -19%) associated with worse outcomes.	12 months
Patient Reported Fatigue	We utilized the Patient Reported Outcomes Information System (PROMIS) Fatigue T-Score. A PROMIS Fatigue T-score of 50 indicates the population mean with a standard deviation of 10. A higher score corresponds to higher levels of reported fatigue.	12 months
Patient Reported Quality of Life	We utilized the Patient Reported Outcomes Information System (PROMIS) Global Health T-score. PROMIS v1.2 Global Health was used to assess physical and mental health. A T-Score of 50 indicates the population mean with a standard deviation of 10. Higher scores indicate better global physical or mental health.	12 months
Patient Reported Symptoms	NCI Patient Reported Outcomes - Common Terms and Criteria for Adverse Events (PRO CTCAE) was used to ascertain presence of 7 symptoms (Shortness of Breath, Cough, Fatigue, Dizziness, Chest Pain, Palpitations, Limb Swelling).	12 months

Collaborators and Investigators

• Sponsor: Abramson Cancer Center at Penn Medicine
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI)
• Investigators: Principal Investigator: Bonnie Ky, MD, MSCE, Perelman School of Medicine at the University of Pennsylvania

Publications and helpful links

General Publications

• Xia C, Smith AM, Lefebvre B, Jamal FA, Armenian SH, Koropeckyj-Cox D, Zhang L, Liu PP, Landsburg D, Clark AS, Shah PD, Hubbard RA, Huang A, Golec S, Hewitt M, Wilcox NS, Chen Z, Rethy L, Jung W, Ko K, Narayan V, Martei YM, Lang NN, Januzzi JL, Felker GM, Ky B. Biomarker-Guided Cardioprotection for Patients Treated With Anthracyclines: A Randomized Clinical Trial. JAMA Netw Open. 2025 Dec 1;8(12):e2546201. doi: 10.1001/jamanetworkopen.2025.46201.

Study record dates

Study Major Dates

• Study Start (Actual): March 18, 2021
• Primary Completion (Actual): February 5, 2025
• Study Completion (Actual): February 5, 2025

Study Registration Dates

• First Submitted: January 28, 2021
• First Submitted That Met QC Criteria: February 2, 2021
• First Posted (Actual): February 3, 2021

Study Record Updates

• Last Update Posted (Actual): June 15, 2026
• Last Update Submitted That Met QC Criteria: June 11, 2026
• Last Verified: June 1, 2026

More Information

Terms related to this study

• Keywords: Cardiomyopathy; Cardio-Oncology; Risk-Guided Intervention; Cardiotoxicity of Chemotherapy
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Wounds and Injuries; Pathologic Processes; Neoplasms by Site; Neoplasms; Heart Diseases; Immune System Diseases; Neoplasms by Histologic Type; Chemically-Induced Disorders; Skin Diseases; Breast Diseases; Lymphatic Diseases; Lymphoproliferative Disorders; Immunoproliferative Disorders; Drug-Related Side Effects and Adverse Reactions; Radiation Injuries; Pathological Conditions, Signs and Symptoms; Skin and Connective Tissue Diseases; Hemic and Lymphatic Diseases; Heart Failure; Breast Neoplasms; Lymphoma; Cardiomyopathies; Cardiotoxicity
• Other Study ID Numbers: UPCC 25920; R21HL152148 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No