Neoplasms

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Breast Neoplasms

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Breast Diseases

Skin Diseases

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Trastuzumab

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Pertuzumab

Ado-Trastuzumab Emtansine

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Antineoplastic Agents, Immunological

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Immunologic Factors

Cardiac intervention - beta-blockers and ACE-inhibitors titrated to the maximum tolerated doses

Oncology intervention - patients will receive one of the three following HER2 targeted therapies at the discretion of the treating oncologist:

* Trastuzumab: loading dose of 8 mg/kg IV, followed by a maintenance dose of 6 mg/kg every 3 weeks, or a loading dose of 4 mg/kg followed by a maintenance dose of 2 mg/kg every week.
* Pertuzumab: loading dose of 840 mg IV, followed by 420 mg IV every 3 weeks, administered concomitantly with trastuzumab.
* Ado trastuzumab emtansine (TDM1): 3.6mg/kg IV every three weeks.

Ado Trastuzumab Emtansine

Sandra M Swain, MD

HER2 positive breast cancer cells have more HER2 receptor (a protein on the surface of cells) than normal breast cells. Approximately 30% of patients with breast cancer have HER2 positive breast cancer. Before HER2 targeted therapies (i.e. treatments that directly block the receptor HER2) were developed, patients with HER2 positive breast cancer had a very aggressive form of disease. With the use of trastuzumab, an anticancer drug that directly targets the receptor HER2, and more recently, pertuzumab and ado-trastuzumab emtansine, patients are able to live longer and have better control of their cancer.

Unfortunately the use of HER2 targeted therapies can increase the risk of heart problems and for this reason these treatments were only studied and approved for patients with normal heart function.

In this study we plan to give HER2 targeted therapies to patients with HER2 positive breast cancer and mildly decreased heart function along with concomitant evaluation by a heart doctor (called cardiologist) and appropriate medications to strengthen the heart. We will do frequent monitoring of the heart function with a test called echocardiogram that will give us a detailed "picture" of the heart. We will also draw blood along with routine blood tests to try to understand why some patients develop heart problems and others do not. The study will take a maximum of 12 months and patients will be monitored for 6 additional months.

We hypothesize that it is safe to administer HER2 targeted therapies to patients with breast cancer and mildly decreased heart function, i.e. LVEF between 40 and 50%, while on appropriate heart medications.

Title: A pilot study evaluating the cardiac safety of HER2 targeted therapy (non-lapatinib) in patients with HER2 positive breast cancer and reduced left ventricular function Phase: Pilot study Study Duration: 4 years with up to 5 additional years of follow up Study Center(s): 3 centers will be participating: MedStar Washington Hospital Center (MWHC), MedStar Georgetown University Hospital (MGUH) and Memorial Sloan Kettering Cancer Center (MSKCC) Primary Objective: To evaluate the cardiac safety of HER2 targeted therapy (non-lapatinib) in patients with HER2 positive breast cancer and reduced left ventricular ejection fraction (LVEF) when given concomitantly with cardiac treatment.

Secondary Objectives:

* To evaluate time to development of cardiac event or asymptomatic worsening of cardiac function
* Absolute changes in LVEF
* Delays in HER2 therapy attributed to cardiac causes
* Correlations between echocardiographic myocardial strain
* cTnI and hs-cTnT at baseline and over time with cardiac events and asymptomatic worsening of cardiac function Sample size: 30 patients

Diagnosis and Main Inclusion Criteria:

* HER2 positive breast cancer, stage I-IV.
* Mildly decreased cardiac function (LVEF between 40 and 49%) prior to or while receiving non-lapatinib HER2 targeted therapy

Cardiac Intervention:

- Beta-blockers and ACE-inhibitors titrated to the maximum tolerated doses

Oncology study Products, Doses, Routes, Regimens:

* Trastuzumab: loading dose of 8 mg/kg IV, followed by a maintenance dose of 6 mg/kg every 3 weeks, or a loading dose of 4 mg/kg followed by a maintenance dose of 2 mg/kg every week.
* Pertuzumab: loading dose of 840 mg IV, followed by 420 mg IV every 3 weeks, administered concomitantly with trastuzumab.
* Ado-trastuzumab emtansine: 3.6mg/kg IV every three weeks. Note: both trastuzumab and pertuzumab may be administered alone or in combination with other systemic or radiation therapy.

Duration of drug administration: Maximum of 12 months.

Cardiac Safety Study in Patients With HER2 + Breast Cancer

SAFE-HEaRt: A Pilot Study Assessing the Cardiac SAFEty of HER2 Targeted Therapy in Patients With HER2 Positive Breast Cancer and Reduced Left Ventricular Function

Cardiac events are defined as any of the following:

* Presence of symptoms attributable to heart failure as confirmed by a cardiologist
* Cardiac arrhythmia requiring pharmacological or electrical treatment
* Myocardial infarction
* Sudden cardiac death or death due to myocardial infarct, arrhythmia or heart failure

Asymptomatic worsening of cardiac function defined as:

- Asymptomatic decline in LVEF \> 10% points from baseline and/or EF \< 35% corroborated by a confirmatory echocardiogram in 2-4 weeks

Planned oncologic therapy is defined as:

* In the adjuvant setting: completion of 1 year total of HER2 targeted therapy. If a patient already received part of the planned HER2 targeted therapy prior to enrollment in this trial, planned oncologic therapy will be achieved when a total of 1 year is completed.
* In the metastatic setting: cessation of treating regimen due to progressive disease or non-cardiac toxicity or non-cardiac death.

Difference in LVEF between end of treatment and baseline

Proportion of patients that had a hold because of symptomatic or asymptomatic cardiotoxicity.

Hold is defined as any delay or discontinuation of HER2 targeted therapy due to cardiac toxicity. One cycle of HER2 targeted therapy will be considered 3 weeks. One therapy hold will be defined as any 3-week HER2 targeted therapy missed dose or 1/3 if one weekly trastuzumab dose. For patients who had a hold and resumed HER2 targeted therapy, duration of treatment hold will be described.

Genentech, Inc.

Medstar Health Research Institute

Cardiac intervention - beta-blockers and ACE-inhibitors titrated to the maximum tolerated doses

Oncology intervention - patients will receive one of the three following HER2 targeted therapies at the discretion of the treating oncologist:

* Trastuzumab: loading dose of 8 mg/kg IV, followed by a maintenance dose of 6 mg/kg every 3 weeks, or a loading dose of 4 mg/kg followed by a maintenance dose of 2 mg/kg every week.
* Pertuzumab: loading dose of 840 mg IV, followed by 420 mg IV every 3 weeks, administered concomitantly with trastuzumab.
* Ado trastuzumab emtansine (TDM1): 3.6mg/kg IV every three weeks.

Trastuzumab: HER2 therapy

Pertuzumab: HER2 therapy

Ado Trastuzumab Emtansine: HER2 therapy

HER2 Therapies, Cardiac Medications

Age, Categorical

Age, Continuous

Sex: Female, Male

Non-Latino Black

Non-Latino White

Hispanic

Race/Ethnicity, Customized

United States

Region of Enrollment

Allison Moses

Percentage of Patients Who Complete Planned Oncologic Therapy Without the Development of a Cardiac Event or Asymptomatic Worsening of Cardiac Function.

Median Time to Development of an Event Defined as Cardiac Event or Asymptomatic Worsening of Left Ventricular Dysfunction, Among Patients Who Developed One Event.

Absolute Changes in LVEF During HER2 Targeted Therapy Between Baseline and End of Treatment

HER2 Therapy Holds Attributed to Proportion of Patients With Symptomatic or Asymptomatic Cardiotoxicity.

There were too few clinical events to assess correlations

Correlation of Global Longitudinal Myocardial Strain With Cardiac Events and Asymptomatic Worsening of Cardiac Function

This outcome was not analyzed. There were too few clinical events to assess correlations.

Correlation of Standard Cardiac Troponin I and Highly Sensitive Cardiac Troponin T With Cardiac Events and Asymptomatic Worsening of Cardiac Function

Overall Study

Antirheumatic Agents

Bone Density Conservation Agents

Anti-Infective Agents

Cyclophosphamide

Docetaxel

Zoledronic Acid

Taxane

Doxorubicin

Liposomal doxorubicin

Anti-Bacterial Agents

Antibiotics, Antitubercular

Enzyme Inhibitors

Zo-Nantax arm - Neoadjuvant chemotherapy with association of zoledronic acid and standard treatment with anthracycline followed taxane plus trastuzumab in locally advanced breast cancer HER2 positive HR positive/negative.

Drug:Cyclophosphamide Drug:Adriamycin Drug:Docetaxel Drug:Trastuzumab Drug:Zolendronic acid

Experimental:

AC,Docetaxel,Trastuzumab,Zolendronate

Drug: AC Adriamycin 60mg/m2 IV plus cyclophosphamide 600mg/m2 every 21 days for 4 cycles

Drug: Docetaxel

Docetaxel 100 mg/m2 every 21 days for 4 cycles.

Drug: Trastuzumab

Trastuzumab 8mg/kg \[loading dose\] once then 6mg/kg IV every 21 days for 3 cycles plus docetaxel.

Drug: zolendronic acid

Zolendronic acid 4mg IV every 21 days for 8 cycles combine with chemotherapy

Zo-Nantax

Susanne C Costa, MD

The purpose of this study is to evaluate the association of zoledronic acid with standard treatment with anthracycline followed taxane plus trastuzumab in locally advanced breast cancer HER 2 positive.

This trial combines zolendronic acid with anthracycline followed taxane plus trastuzumab for neoadjuvant treatment of HER 2 positive stage II/III breast cancer.

Zoledronic acid (ZOL) has activity of anti-bone resorption and shows diverse anti-tumor effects in vitro. Some chemical and biological characteristics of ZOL indicate potential for inhibition of tumor growth in pre clinical studies

The primary objective of the study is to evaluate the residual cancer burden (RCB) with the addition of zolendronic acid to standard neoadjuvant therapy. RCB is calculated as a continuous index combining pathologic measurements of primary tumor (size and cellularity) and nodal metastases (number and size). RCB index is a significant predictor of distant relapse-free survival, and can be used to define categories of near-complete response and chemotherapy resistance after neoadjuvant chemotherapy compared with currently used risk factors. Additionally, the study will collect tissue biopsies and blood before and after treatment in order to correlate clinical outcomes with gene expression and radiologic data to predictive response.

ZoNantax - Zolendronic Acid as Neoadjuvant Therapy Plus Anthracycline and Taxane in Locally Advanced Breast Cancer

Phase II Clinical Trial of Neoadjuvant Treatment With Zolendronic Acid Plus Anthracycline and Taxane in Locally Advanced Breast Cancer

Use MD Anderson calculator to quantify the minimal residual disease

Make MRI before the start of chemotherapy, after the second cycle and before surgery, and evaluate the changes in the diffusion of water

Susanne Crocamo

Clinical Oncologist

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Cardiac Safety Study in Patients With HER2 + Breast Cancer	NCT01904903	HER2 Positive B... Left Ventricula...	Trastuzumab Pertuzumab Ado Trastuzumab...	18 Years - 120 Years	Medstar Health Research Institute
ZoNantax - Zolendronic Acid as Neoadjuvant Therapy Plus Anthracycline and Taxane in Locally Advanced Breast Cancer	NCT01472146	Breast Cancer Breast Disease Neoplasms Neoplasms by Si...	Zo-Nantax	18 Years - 75 Years	Instituto Nacional de Cancer, Brazil
Cardiac Safety Study in Patients With HER2 + Breast Cancer	NCT01904903	HER2 Positive B... Left Ventricula...	Trastuzumab Pertuzumab Ado Trastuzumab...	18 Years - 120 Years	Medstar Health Research Institute
ZoNantax - Zolendronic Acid as Neoadjuvant Therapy Plus Anthracycline and Taxane in Locally Advanced Breast Cancer	NCT01472146	Breast Cancer Breast Disease Neoplasms Neoplasms by Si...	Zo-Nantax	18 Years - 75 Years	Instituto Nacional de Cancer, Brazil

Spots Global Cancer Trial Database for breast cancer her2 positive