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A Prospective Study of Breast Cancer Patients With Abnormal Strain Imaging

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT02993198
Recruitment Status : Recruiting
First Posted : December 15, 2016
Last Update Posted : March 3, 2020
Information provided by (Responsible Party):
Nausheen Akhter, Northwestern University

Brief Summary:

The Cardio-Oncology program at Northwestern offers care to cancer patients who develop cardiac toxicities from chemotherapy. Breast cancer patients with the tumor marker for HER2 necessitate treatment with anthracycline and/or trastuzumab and pertuzumab-based chemotherapies, which are known to cause cardiac toxicities. Breast cancer patients will undergo a "cardio-oncology echocardiogram" which incorporates advanced left ventricular assessment by utilizing deformation or strain imaging during chemotherapy treatment for surveillance of cardiac toxicities. The aims of this project are:

  1. To create a registry of both clinical, and echocardiographic variables, biomarkers, and genetic analysis that will be used to develop a risk model to predict LV dysfunction in early stage breast cancer patients undergoing chemotherapy with anthracycline and/or trastuzumab and pertuzumab-based chemotherapy regimens.
  2. To propose a new management algorithm for initiation of prophylactic beta-blocker therapy for early stage breast cancer patients with preclinical cardiac toxicities demonstrated by strain parameters.
  3. To determine if initiation of prophylactic beta-blocker therapy in patients with early cardiac toxicity can delay or prevent a drop in LV EF and the development of clinical heart failure.
  4. To explore serial measurements of a suite of novel biomarkers during ongoing anticancer treatment that are presumed but not yet proven to be predictive of cardiac dysfunction in women with breast cancer.
  5. To identify DNA biomarkers of predilection to cardiotoxicity.
  6. To generate hiPSC to validate markers predictive of cardiotoxicity.

Condition or disease Intervention/treatment Phase
HER2 Positive Breast Cancer Cardiovascular Abnormalities Drug: Carvedilol Phase 2

Detailed Description:

150 patients will be prospectively consented/screened. Over the course of the study, 30 patients are expected to develop abnormal strain with a normal EF > 53%. They will be randomized in 1:1 fashion to open label carvedilol vs. no treatment.

All consenting patients will receive a baseline echocardiogram and blood draw for biomarkers and genetic testing. Patients will be followed with echocardiograms at 3 month intervals for 12 months, until completion of trastuzumab/pertuzumab therapy.

Based on echocardiogram findings, patient will fall into four study arms (A, B, C, D). Patients in Arm A (normal EF and normal strain) and Arm D (decrease in EF > 10%, to a value <53%) will receive current standard of care treatment and will be followed in a registry arm. Arms B and C will comprise of 30 patients with normal EF who develop preclinical cardiac dysfunction, as defined as a change in global longitudinal strain of > 15% from baseline strain) or < -15% absolute longitudinal strain will be prospectively assigned 1:1 to receive prophylactic carvedilol (Arm B) vs. no treatment (Arm C). Prophylactic carvedilol will be initiated at the starting dose of 3.125 mg PO BID and titrated based on blood pressure and heart rate.

Patients will be seen every 3 weeks during the titration phase at their chemotherapy appointments. At each visit, vitals and symptoms will be assessed for dizziness and side-effects from carvedilol. If patient complains of dizziness or HR < 50 bpm, or SBP < 100 mmHg, then the dose titration should stop and the dose should be reduced to the dose at the last increased increment. If there is a > 10% decrease in EF to a value < 53% on the next echocardiogram, then standard heart failure therapy will be initiated (beta-blocker and/or ace-inhibitors) and chemotherapy will be held as per standard of care. If patients require other standard of care treatments for heart failure, such as diuretic therapy or aldosterone antagonists, then this will also be initiated. At this point, these patients will be considered to have met the study endpoint. However, if there is an improvement or no change in strain and EF, then patients will continue with cardiac surveillance with an echo at 3 month intervals. Patients who have been assigned to receive prophylactic carvedilol will continue treatment for duration of chemotherapy up to 1 year. Prophylactic carvedilol will be stopped at the completion of study.

A biomarker substudy will be conducted on 100 patients. These patients will have labs drawn every at ten time points, baseline and every 6 weeks for 12 months, and 1 year post-chemotherapy. A separate blood draw for generation of hiPSC and DNA testing would be done for 100 patients. The blood collection will coincide with the patient's chemotherapy infusions with trastuzumab. These biomarkers will allow for further characterization of patients at risk for developing CTRCD.

A "cardio-oncology" echocardiogram will include standard 2D M-mode and Doppler echocardiography, 2D strain imaging, and 3D LV volume. This data will be processed on-line or off-line within 24 hours of completion of the echocardiogram to determine randomization.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 150 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Prevention
Official Title: A Prospective Study of Early Stage Breast Cancer Patients With Abnormal Myocardial Deformation Treated With Anthracycline and/or Trastuzumab and Pertuzumab-based Cancer Therapy
Study Start Date : April 2015
Estimated Primary Completion Date : December 2021
Estimated Study Completion Date : December 2021

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Breast Cancer
Drug Information available for: Carvedilol

Arm Intervention/treatment
Experimental: Prophylactic Carvedilol
Carvedilol 3.125 mg by mouth every 12 hours, titrated to a max dose of 25 mg by mouth every 12 hours, depending on blood pressure and heart rate, until completion of study.
Drug: Carvedilol
No Intervention: No Therapy
Standard of care monitoring without prophylactic treatment.

Primary Outcome Measures :
  1. Change in Global Longitudinal Strain [ Time Frame: 1 year ]
    Improvement or stability in strain from baseline (i.e., increase in strain or decrease by no more than 3%).

Secondary Outcome Measures :
  1. Number of cancer treatments [ Time Frame: 1 year ]
    Rate of cancer treatments held for decrement in EF > 10% among groups.

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  1. Patients > 18 years of age with HER2-overexpressing early stage breast cancer (Stages I - III)
  2. Pathology report must include HER2 expression, estrogen and progesterone receptor status
  3. Normal LV function (EF > 53%) on baseline echocardiogram
  4. NYHA functional class I-II (no symptoms, dyspnea with more than 2 blocks)
  5. Scheduled to receive treatment with anthracycline and/or trastuzumab and pertuzumab-based regimens
  6. Patients with a history of HTN, hyperlipidemia, diabetes, mild CAD, mild valvular disease are permitted
  7. Patients on concomitant cardiac medications other than beta-blockers (BB) or ace-inhibitors (ACE) therapy are permitted. Other non-cardiac medications are not prohibited.
  8. Women of childbearing potential and sexually active men and women should use effective contraception.
  9. Patients must have a signed informed consent prior to registration

Exclusion Criteria:

  1. LV dysfunction (EF < 53%)
  2. New York Heart Association (NYHA) functional class III-IV (heart failure symptoms at less than 2 blocks to advanced symptoms at rest)

    a. NYHA Classification: I - No limitations to activity II - Slight limitation to ordinary activity, no symptoms at rest III - Marked limitation to less than ordinary activity, no symptoms at rest IV - Inability to carry out activity without symptoms, symptoms at rest

  3. Pre-existing cardiac disease (moderate-severe coronary artery disease, moderate-severe valvular heart disease, constrictive/restrictive cardiomyopathies)
  4. Metastatic breast cancer
  5. Patients who have ever taken BB/ACE therapy are excluded.
  6. 2nd and 3rd degree AV block
  7. Sick sinus syndrome
  8. Patients with severe bradycardia (< 50 bpm) or severe hypotension (SBP < 85 mmHg)
  9. Severe liver dysfunction defined as Child-Turcotte-Pugh class B & C (significant functional compromise - decompensated disease)
  10. Moderate-severe Asthma
  11. Hypersensitivity to beta-blockers
  12. Patients who are pregnant/lactating are not eligible
  13. Unwilling to consent/assent to blood donation

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT02993198

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Contact: Caitlin Brady, MS (312)926-5968

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United States, Illinois
Northwestern University Recruiting
Chicago, Illinois, United States, 60611
Contact: Caitlin Brady, MS    312-926-5968   
Principal Investigator: Nausheen Akhter, MD         
Sponsors and Collaborators
Northwestern University
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Responsible Party: Nausheen Akhter, Assistant Professor of Medicine, Northwestern University Identifier: NCT02993198    
Other Study ID Numbers: STU00200675
First Posted: December 15, 2016    Key Record Dates
Last Update Posted: March 3, 2020
Last Verified: February 2020
Additional relevant MeSH terms:
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Breast Neoplasms
Cardiovascular Abnormalities
Neoplasms by Site
Breast Diseases
Skin Diseases
Congenital Abnormalities
Cardiovascular Diseases
Adrenergic beta-Antagonists
Adrenergic Antagonists
Adrenergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs
Antihypertensive Agents
Protective Agents
Calcium Channel Blockers
Membrane Transport Modulators
Calcium-Regulating Hormones and Agents
Vasodilator Agents
Adrenergic alpha-1 Receptor Antagonists
Adrenergic alpha-Antagonists