Efficacy and Safety Study of EG12014 Compared With Herceptin in Subjects With HER2 Positive Early Breast Cancer

Study Overview
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Brief Summary
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The purpose of this research study is to compare the efficacy and safety of EG12014 with Herceptin as neoadjuvant treatment for 12 weeks, followed by surgery and subsequent EG12014 or Herceptin adjuvant treatment for up to 12 months.

Official Title
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A Phase III, Randomized, Multicenter, Double-blind Study to Compare Efficacy and Safety of EG12014 With Herceptin as Neoadjuvant Treatment in Combination With Anthracycline/Paclitaxel Systemic Therapy in HER2-Positive Early Breast Cancer

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: EG12014
* Drug: Herceptin


Participation Criteria
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Eligibility Criteria
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Provide signed and dated written informed consent before entering the study. The informed consent will cover both parts of the study (neoadjuvant part and adjuvant part). Female, ≥18 and ≤65 years of age. Histologically-confirmed invasive carcinoma of the breast (American Joint Committee on Cancer [AJCC, vs. 8.0] Stage II, IIIa). Operable breast cancer, planned surgical resection of breast tumor (mastectomy or lumpectomy) and sentinel or axillary lymph nodes. Unilateral, measurable tumor of the breast >2 cm in diameter. HER2 positive tumor, defined as 3+ score by IHC or fluorescence positive by FISH, as confirmed by central laboratory. Known estrogen receptor (ER) and progesterone receptor (PrR) status at study entry. Adequate bone marrow function, defined as granulocyte count of ≥1.500/µL, and platelet count of ≥100.000/µL. Adequate hepatic and renal function, defined as: bilirubin within normal range alanine aminotransferase (ALT) ≤2 x upper limit of normal (ULN) aspartate aminotransferase (AST) ≤2 x ULN gamma glutamyl transferase (GGT) ≤3 x ULN serum creatinine <1.5 ULN International normalized ratio ≤1.5×ULN (2 to 3×ULN if on anticoagulants) or prothrombin time ≤1.5×ULN; activated partial thromboplastin time ≤1.5×ULN. Hemoglobin concentrations ≥10 g/dL. Eastern Cooperative Oncology Group (ECOG) score of 0 or 1. LVEF ≥55%, measured by multiple-gated acquisition (MUGA) scan or echocardiography. Negative pregnancy test at entry, women of childbearing potential have to use contraceptives during the course of the study. Females with childbearing potential must provide a negative serum pregnancy test at Screening and must be using adequate birth control. Adequate birth control is defined as agreement to consistently practice an effective and accepted method of contraception throughout the duration of the study and for 7 months after study drug treatment. These methods include hormonal contraceptives, intrauterine device, or double barrier contraception (i.e., condom + diaphragm) or a male partner with documented vasectomy. Non-childbearing potential is defined as post-menopausal for at least 1 year or surgical sterilization or hysterectomy at least 3 months before study start. Exclusion Criteria: Bilateral breast cancer. Pregnancy or lactation or considering becoming pregnant. Metastases, other than sentinel/axillary lymph nodes. Previous treatment (chemotherapy, biologic therapy, radiation, or surgery) for invasive malignant disease or other concomitant malignancy, other than basal cell carcinoma of the skin. Previous treatment for carcinoma in situ of the cervix is allowed. Previous treatment with Herceptin. Angina pectoris or arrhythmia requiring medication; poorly controlled hypertension; history of myocardial infarction or cardiac failure, New York Heart Association (NYHA) class II or higher; clinically significant cardiac valvular disease; hemodynamic effective pericardial effusion; other cardiomyopathies; LVEF of <55%. Any investigational treatment less than 30 days prior to study entry, or within a time interval less than at least 5 half-lives of the investigational medicinal product, whichever is longer. Positive diagnostic test for hepatitis B virus (HBV), hepatitis C virus (HCV), or human immunodeficiency virus (HIV). History of hypersensitivity to drugs with similar chemical structures to trastuzumab. History of, or known current problems with, drug or alcohol abuse. Other serious illness, medical disorder or condition that, in the opinion of the Investigator, would make the patient unsuitable for participation in the study.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: EG12014<br>Epirubicin and cyclophosphamide followed by EG12014 plus paclitaxel. All patients will be scheduled for surgery (breast and axillary lymph nodes) at 3 to 6 weeks after completion of neoadjuvant chemotherapy. | Drug: EG12014<br>* EG12014 6mg/kg is ongoing to be administered after 8mg/kg loading dose.<br>|
| Active Comparator: Herceptin<br>Epirubicin and cyclophosphamide followed by Herceptin plus paclitaxel. All patients will be scheduled for surgery (breast and axillary lymph nodes) at 3 to 6 weeks after completion of neoadjuvant chemotherapy. | Drug: Herceptin<br>* Herceptin 6mg/kg is ongoing to be administered after 8mg/kg loading dose.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Determination of pathologic complete response (pCR) at time of surgery | pCR is defined as the absence of residual invasive cancer on hematoxylin and eosin evaluation of the complete resected breast specimen and all sampled sentinel and/or axillary lymph nodes | At the time of surgery (3-6 weeks after completion of neoadjuvant chemotherapy) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| pCR at the time of surgery | pCR is defined as the absence of residual invasive cancer and of DICS (ypT0 ypN0) from breast tissue and sentinel/axillary lymph nodes, as assessed by central laboratory | At the time of surgery (3-6 weeks after completion of neoadjuvant chemotherapy) | 
| pCR at the time of surgery | pCR is defined as the absence of invasive cancer in breast tissue only (ypT0/is) as assessed by central laboratory | At the time of surgery (3-6 weeks after completion of neoadjuvant chemotherapy) | 
| Event-free survival (EFS) up to end of study (EOS) | EFS is defined as time from initial randomization to the date when disease recurrence or progression (local, regional, distant or contralateral) is diagnosed according to institutional standard, or date of death of any cause, whichever is earlier | Randomization to date of progression or end of study (up to approximately 24 months or death) | 
| Overall response (OR) prior to surgery | Objective response is defined as partial response (PR) or complete response (CR) according to RECIST v1.1 | At screening and prior to surgery (3-6 weeks after completion of neoadjuvant chemotherapy) | 
| Overall survival (OS) up to End of Study (EOS) | OS up to EOS is defined as time from the date of initial randomization to the date of death | Randomization to end of study (up to approximately 24 months or death) | 
| Incidence of AEs | Incidence of AEs (including severity, seriousness, and relationship to study drug) and laboratory abnormalities | From time of informed consent to end of study (up to approximately 25 months or death) | 
| Evaluation of Immunogenicity of EG12014 and Herceptin | Titer of anti-drug antibodies (ADA) | Prior to 1st infusion of study drug, during neoadjuvant treatment, after the last dose of neoadjuvant treatment, during adjuvant treatment, and End of Treatment | 
| Measure serum trastuzumab concentration | Measure serum trastuzumab concentration for EG12014 and Herceptin arms | Prior to 1st infusion of study drug, during neoadjuvant treatment after the last dose of neoadjuvant treatment, during adjuvant treatment, and End of Treatment |