Clinical Trials /

A Prospective Study of Breast Cancer Patients With Abnormal Strain Imaging

NCT02993198

Description:

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.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: A Prospective Study of Breast Cancer Patients With Abnormal Strain Imaging
  • 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

Clinical Trial IDs

  • ORG STUDY ID: STU00200675
  • NCT ID: NCT02993198

Conditions

  • HER2 Positive Breast Cancer
  • Cardiovascular Abnormalities

Interventions

DrugSynonymsArms
CarvedilolProphylactic Carvedilol

Purpose

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.

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.
    

Trial Arms

NameTypeDescriptionInterventions
Prophylactic CarvedilolExperimentalCarvedilol 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.
  • Carvedilol
No TherapyNo InterventionStandard of care monitoring without prophylactic treatment.

    Eligibility Criteria

            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
          
    Maximum Eligible Age:N/A
    Minimum Eligible Age:18 Years
    Eligible Gender:Female
    Healthy Volunteers:No

    Primary Outcome Measures

    Measure:Change in Global Longitudinal Strain
    Time Frame:1 year
    Safety Issue:
    Description:Improvement or stability in strain from baseline (i.e., increase in strain or decrease by no more than 3%).

    Secondary Outcome Measures

    Measure:Number of cancer treatments
    Time Frame:1 year
    Safety Issue:
    Description:Rate of cancer treatments held for decrement in EF > 10% among groups.

    Details

    Phase:Phase 2
    Primary Purpose:Interventional
    Overall Status:Recruiting
    Lead Sponsor:Northwestern University

    Last Updated

    June 23, 2017