Breast Cancer, Cardiomyopathies, Cardiotoxicity, Heart Failure, Lymphoma, Toxicity Due to Chemotherapy
Conditions
Keywords
Risk-Guided Intervention, Cardiotoxicity of Chemotherapy, Cardio-Oncology, Cardiomyopathy
Brief summary
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.
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.
Interventions
OTHERBiomarker 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.
Sponsors
Abramson Cancer Center at Penn Medicine
National Heart, Lung, and Blood Institute (NHLBI)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
NONE
Intervention model description
Serial monitoring of NTproBNP during chemotherapy will be used to identify high-risk patients in the intervention arm; patients who experience elevations in NTproBNP will be initiated and titrated on a personalized regimen of neurohormonal antagonists. Patients in the usual care arm will not have serial NTproBNP monitoring and will be managed according to usual care.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Recruitment Rate | At baseline | percent of patients approached about the study who provided consent |
| Retention Rate | Through study completion (expected to be 1 year) | percent of randomized patients who complete the study per protocol |
| Compliance Rate | Through study completion (expected to be 1 year) | 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). |
| Maximum Dose | Through study completion (expected to be 1 year) | 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). |
| Incidence of Adverse Events | 12 months | Number of patients that had at least one targeted AE of grade 3 or higher at any time on study. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in NTproBNP | Through study completion (1 year) | 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. |
| Change in Left Ventricular Ejection Fraction (LVEF) | 12 months | 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. |
| Incidence of Cardiotoxicity | 12 months | Incidence of cardiotoxicity defined as LVEF decline of at least 10% to less than 50% |
| Incidence of Heart Failure (HF) | 12 months | Incidence of new or worsened clinical heart failure, defined as urgent or new office or emergency department visit or hospitalization for adjudicated heart failure. |
| Frequency of Cancer Treatment Interruptions | Through study completion (expected to be 1 year) | Frequency of cancer treatment interruptions (holds or early discontinuations) |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORBonnie Ky, MD, MSCE
Perelman School of Medicine at the University of Pennsylvania
Participant flow
Recruitment details
Enrollment took place from March 2021 to October 2023 from outpatient oncology practices at multiple locations within the University of Pennsylvania Health System and at City of Hope Cancer Center.
Pre-assignment details
108 individuals provided consent. 7 individuals were not randomized due to 1 of the following reasons: voluntary withdrawal, change in chemotherapy regimen, or uncontrolled blood pressure. 101 patients were randomized and started the trial.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 50.0 years STANDARD_DEVIATION 15.9 |
| Body Mass Index (BMI) | 28.1 kg/m2 |
| Cancer Type Breast Cancer | 37 Participants |
| Cancer Type Lymphoma | 13 Participants |
| Cardiovascular Risk Factors Coronary Disease | 4 Participants |
| Cardiovascular Risk Factors Current and Prior Smokers | 42 Participants |
| Cardiovascular Risk Factors Diabetes | 4 Participants |
| Cardiovascular Risk Factors Hyperlipidemia | 16 Participants |
| Cardiovascular Risk Factors Hypertension | 33 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 6 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 44 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Left Ventricular Ejection Fraction | 59.1 % |
| NTproBNP Concentration | 54 pg/ml |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 6 Participants |
| Race (NIH/OMB) Black or African American | 5 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) White | 77 Participants |
| Sex: Female, Male Female | 42 Participants |
| Sex: Female, Male Male | 8 Participants |
| Systolic Blood Pressure | 125 mmHg |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 50 | 4 / 50 |
| other Total, other adverse events | 47 / 50 | 46 / 50 |
| serious Total, serious adverse events | 9 / 50 | 14 / 50 |
Outcome results
None listed