## Protocol Section
### Identification Module
**NCT ID:** NCT02101879

**Brief Title:** Cardiotoxicity in Metastatic Her 2 Positive Patients Treated With Trastuzumab ,Pertuzumab and Taxanes

**Official Title:** Cardiotoxicity in Metastatic Her 2 Positive Patients Treated With First Line Trastuzumab, Pertuzumab and Taxanes Based Regimen

#### Organization Study ID Info
**ID:** Cardiotoxicity
#### Organization
**Class:** OTHER
**Full Name:** Rambam Health Care Campus
### Status Module
#### Completion Date
**Date:** 2016-08

**Type:** ESTIMATED

#### Expanded Access Info
**Last Known Status:** RECRUITING
#### Last Update Post Date
**Date:** 2014-05-02

**Type:** ESTIMATED

**Last Update Submit Date:** 2014-05-01

**Overall Status:** UNKNOWN

#### Primary Completion Date
**Date:** 2016-03

**Type:** ESTIMATED

#### Start Date
**Date:** 2014-05

**Status Verified Date:** 2014-05

#### Study First Post Date
**Date:** 2014-04-02
**Type:** ESTIMATED
**Study First Submit Date:** 2014-03-05
**Study First Submit QC Date:** 2014-03-30
### Sponsor Collaborators Module

#### Lead Sponsor

**Class:** OTHER

**Name:** Rambam Health Care Campus

#### Responsible Party

**Type:** SPONSOR

### Oversight Module

**Oversight Has DMC:** False

### Description Module

**Brief Summary:** Approximately 15-25% of all breast cancers are human epidermal growth factor receptor 2 (HER2) positive and it has been well known that HER2 overexpression is associated with more aggressive phenotype and poor prognosis with resistance to certain chemotherapeutic agents.

Trastuzumab administration as an adjuvant and in metastatic HER2 positive breast cancer is associated with both symptomatic and asymptomatic cardiotoxicity. The incidence of trastuzumab-mediated cardiotoxicity were 27% with antracycline combination and 13% when it was administered with paclitaxel .

Pertuzumab, a recombinant humanized monoclonal antibody binding to the HER2 dimerization domain, prevents dimerization of HER2 with other HER receptors (HER3,HER1, and HER4) especially with HER3. Blocking HER2-HER3 dimerization is postulated to be the most clinically relevant action of pertuzumab and this can effectively block her2-mediated cell signaling.

Pertuzumab is indicated in combination with trastuzumab and docetaxel for the treatment of patients with HER2-positive metastatic breast cancer who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease.

Treatment of breast cancer with pertuzumab plus trastuzumab plus docetaxel as first line treatment until disease progression might be complicated by cardiotoxicity in up to 14.5% of the Patients.

Cardinale et al showed that troponin I (TNI) positive identifies trastuzumab-treated patients who are at risk for cardiotoxicity and are unlikely to recover from cardiac dysfunction despite HF therapy.

There is very little data about the reversibility and identification of patients at risk for cardiotoxicity of the pertuzumab plus trastuzumab plus docetaxel regimen and of those who will not recover from cardiac dysfunction,this information is crucial. The usefulness of troponin I (TNI) and Brain natriuretic peptide (BNP) in the identification of patients at risk for PT cardiotoxicity and in the prediction of LVEF recovery has never been investigated.

based on this background , this study aim is to evaluate the cardiotoxicity of pertuzumab plus trastuzumab plus docetaxel regimen and the application of troponin I (TNI) and Brain natriuretic peptide (BNP) in this setting.

**Detailed Description:** Breast cancer is the leading cancer in women in Israel with 4000 new cases every year.

Approximately 15-25% of all breast cancers are human epidermal growth factor receptor 2 (HER2) positive and it has been well known that HER2 overexpression is associated with more aggressive phenotype and poor prognosis with resistance to certain chemotherapeutic agents.

Trastuzumab, an anti-HER2 humanized monoclonal antibody, is the standard treatment for both early and metastatic HER2-positive breast cancer. In addition to other chemotherapeutic agents, trastuzumab significantly improves response rate and survival in HER2-positive early and metastatic breast cancer. Although it is well known that trastuzumab therapy is closely associated with both symptomatic and asymptomatic cardiotoxicity.

Addition of trastuzumab to chemotherapy significantly improved response rate, time to disease progression and reduction of death compared to chemotherapy alone in HER2-positive metastatic breast cancer (MBC). Thus, anti-HER2 treatment is a standard therapeutic approach for HER2-positive MBC patients with visceral crisis. Trastuzumab administration as an adjuvant and in metastatic HER2 positive breast cancer is associated with both symptomatic and asymptomatic cardiotoxicity. The incidence of trastuzumab-mediated cardiotoxicity were 27% with antracycline combination and 13% when it was administered with paclitaxel .

Pertuzumab, a recombinant humanized monoclonal antibody binding to the HER2 dimerization domain, prevents dimerization of HER2 with other HER receptors (HER3,HER1, and HER4) especially with HER3. Pertuzumab differs from trastuzumab in the epitope binding regions of the light chain; pertuzumab binds to domain 2 ofHER2 essential for dimerization, whereas trastuzumab binds to domain 4 of HER2. Blocking HER2-HER3 dimerization is postulated to be the most clinically relevant action of pertuzumab and this can effectively block her2-mediated cell signaling.

Pertuzumab is indicated in combination with trastuzumab and docetaxel for the treatment of patients with HER2-positive metastatic breast cancer who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease.

The randomized, double-blind, placebo controlled,phase III CLEOPATRA (the CLinical Evaluation OfPertuzumab And Trastuzumab) study involved 808 patients with HER2-positive MBC who had not received prior chemotherapy or biologic therapy, who were randomized to placebo plus trastuzumab plus docetaxel or pertuzumab plus trastuzumab plus docetaxel as first line treatment until disease progression. No additional cardiotoxicity was observed when adding pertuzumab compared to placebo. The incidence of any cardiac disorder as assessed by the investigators was similar in the placebo (16.4%) and pertuzumab (14.5%) arms. Left ventricular systolic dysfunction (LVSD) was observed in 8.3% and 4.4% of placebo and pertuzumab patients, respectively. Left ventricular systolic dysfunction of grade III or higher was reported in 7 (1.8%) patients in the placebo arm and 4 (1.0%) in the pertuzumab arm.

Treatment of breast cancer with pertuzumab plus trastuzumab plus docetaxel as first line treatment until disease progression might be complicated by cardiotoxicity in up to 14.5% of the Patients.

Cardinale et al showed that troponin I (TNI) positive identifies trastuzumab-treated patients who are at risk for cardiotoxicity and are unlikely to recover from cardiac dysfunction despite HF therapy.

There is very little data about the reversibility and identification of patients at risk for cardiotoxicity of the pertuzumab plus trastuzumab plus docetaxel regimen and of those who will not recover from cardiac dysfunction,this information is crucial. The usefulness of troponin I (TNI) and Brain natriuretic peptide (BNP) in the identification of patients at risk for PT cardiotoxicity and in the prediction of LVEF recovery has never been investigated.

based on this background , this study aim is to evaluate the cardiotoxicity of pertuzumab plus trastuzumab plus docetaxel regimen and the application of troponin I (TNI) and Brain natriuretic peptide (BNP) in this setting.

### Conditions Module

**Conditions:**

- Cardiotoxicity.

- Anti Her2 Therapy.

- Metastatic Breast Cancer

### Design Module

#### Bio Spec

**Description:** Blood samples for TNI \& BNP will be sent before every cycle for the first 5 cycles of treatment

**Retention:** SAMPLES_WITHOUT_DNA

#### Design Info

**Observational Model:** COHORT

**Time Perspective:** PROSPECTIVE

#### Enrollment Info

**Count:** 20

**Type:** ESTIMATED

**Patient Registry:** True

**Study Type:** OBSERVATIONAL

**Target Duration:** 12 Months

### Arms Interventions Module

#### Arm Group 1

**Description:** Trastuzumab \& Pertuzumab \& Taxanes

**Label:** Breast cancer Her2 positive

### Outcomes Module

#### Primary Outcomes

**Description:** Prior to every treatment cycle, blood samples will be taken for TNI \& BNP. Patients with elevated levels will be sent for LEVF evaluation. In cases with LEVF reduction of 15% or more from the baseline or LEVF less than 50% will be sent for Cardiological consult in order to consider ACEI or BB treatment

**Measure:** To assesses blood levels of TNI and BNP during the first four cycles Trastuzumab&Pertuzumab and Taxanes treatment

**Time Frame:** The patients will be followed until the end of therapy (an expected average of 18 months).

**Description:** Prior to every treatment cycle, blood samples will be taken for TNI \& BNP. Patients with elevated levels will be sent for LEVF evaluation. In cases with LEVF reduction of 15% or more from the baseline or LEVF less than 50% will be sent for Cardiological consult in order to consider ACEI or BB treatment

**Measure:** To evaluate the correlation between elevated TNI&BNP and decline of LVEF on echocardiography until end of treatment.

**Time Frame:** The patients will be followed until the end of therapy (an expected average of 18 months).

### Eligibility Module

**Eligibility Criteria:** Inclusion Criteria:

* Metastatic Breast Cancer patients with Her2 Positive Disease.
* No prior treatment

Exclusion Criteria:

* LEVF less than 50%

**Minimum Age:** 18 Years

**Sampling Method:** PROBABILITY_SAMPLE

**Sex:** FEMALE

**Standard Ages:**

- ADULT

- OLDER_ADULT

**Study Population:** Patients with Metastatic Breast Cancer Her2 Positive

### Contacts Locations Module

#### Central Contacts

**Contact 1:**

**Email:** g_fried@rambam.health.gov.il

**Name:** Georgeta Fried, MD

**Phone:** +972-4-854-3018

**Role:** CONTACT

#### Locations

**Location 1:**

**City:** Haifa

**Contacts:**

***Contact 1:***

- **Name:** Georgeta Fried, MD

- **Role:** PRINCIPAL_INVESTIGATOR

***Contact 2:***

- **Name:** Shlomit Shachar-Strulov, MD

- **Role:** SUB_INVESTIGATOR

**Country:** Israel

**Facility:** Rambam MC

**Status:** RECRUITING

## Derived Section

### Condition Browse Module - Ancestors

- ID: D000006331

- Term: Heart Diseases

- ID: D000002318

- Term: Cardiovascular Diseases

- ID: D000010335

- Term: Pathologic Processes

- ID: D000064420

- Term: Drug-Related Side Effects and Adverse Reactions

- ID: D000064419

- Term: Chemically-Induced Disorders

- ID: D000011832

- Term: Radiation Injuries

- ID: D000014947

- Term: Wounds and Injuries

### Condition Browse Module - Browse Branches

- Abbrev: BC04

- Name: Neoplasms

- Abbrev: BC17

- Name: Skin and Connective Tissue Diseases

- Abbrev: All

- Name: All Conditions

- Abbrev: BC14

- Name: Heart and Blood Diseases

- Abbrev: BC23

- Name: Symptoms and General Pathology

- Abbrev: BC25

- Name: Substance Related Disorders

- Abbrev: BC26

- Name: Wounds and Injuries

### Condition Browse Module - Browse Leaves

- ID: M5220

- Name: Breast Neoplasms

- Relevance: LOW

- As Found: Unknown

- ID: M30670

- Name: Cardiotoxicity

- Relevance: HIGH

- As Found: Cardiotoxicity

- ID: M9419

- Name: Heart Diseases

- Relevance: LOW

- As Found: Unknown

- ID: M30303

- Name: Drug-Related Side Effects and Adverse Reactions

- Relevance: LOW

- As Found: Unknown

- ID: M30302

- Name: Chemically-Induced Disorders

- Relevance: LOW

- As Found: Unknown

- ID: M14679

- Name: Radiation Injuries

- Relevance: LOW

- As Found: Unknown

- ID: M17685

- Name: Wounds and Injuries

- Relevance: LOW

- As Found: Unknown

### Condition Browse Module - Meshes

- ID: D000066126

- Term: Cardiotoxicity

### Intervention Browse Module - Browse Branches

- Abbrev: ANeo

- Name: Antineoplastic Agents

- Abbrev: All

- Name: All Drugs and Chemicals

### Intervention Browse Module - Browse Leaves

- ID: M325

- Name: Trastuzumab

- Relevance: LOW

- As Found: Unknown

- ID: M147959

- Name: Taxane

- Relevance: LOW

- As Found: Unknown

- ID: M289243

- Name: Pertuzumab

- Relevance: LOW

- As Found: Unknown

### Misc Info Module

- Version Holder: 2024-05-24
