A multicenter, double-blind, randomized, parallel-group, Phase III study of the efficacy and safety of Hercules( Myl 1401O, Mylan Trastuzumab) plus taxane versus Herceptin® plus taxane as first line therapy in patients with HER2-positive metastatic breast cancer.

Part 1: A multicenter, double-blind, randomized, parallel-group, Phase III study to compare the efficacy and safety of MYL-1401O (Mylan Trastuzumab biosimiliar) plus taxane versus Herceptin® plus taxane in patients with HER2+ MBC. Either docetaxel or paclitaxel (Investigator site level choice) is planned for at least 24 weeks until documented response to therapy, disease progression, or discontinuation. Disease response and progression will be assessed locally by the Investigator on the basis of clinical and radiographic evidence using RECIST 1.1 criteria. The primary and secondary efficacy analyses will be performed using independently assessed radiographic evidence for the Intent-to-Treat (ITT) population. The primary analysis population for best ORR will be those patients who had measureable disease at baseline and for the secondary endpoint, DR, only those who are responders will be included in the analysis.

Part 2: A multicenter, double-blind, parallel-group study to continue to compare the safety and immunogenicity and efficacy of MYL-1401O versus Herceptin® in patients with HER2+ MBC who have clinical benefit to first-line combination therapy with a taxane. All patients who have at least stable disease (SD), will continue with either single agent MYL-1401O or Herceptin® alone until death, unacceptable toxicity or disease progression.

Population pharmacokinetics: During Part 1 of the study, for both MYL-1401O, and Herceptin® treatment arms, PK sampling for Cmin and Cmax (end of infusion) will be collected for all patients. A PopPK subset, with sufficient samples available to perform the necessary analysis of PopPK modeling will be used to assess AUC, Cmax, Cmin, clearance, Vd, and T1/2 at various time points in the PopPK. Patients randomized into the main study will sign an additional consent form for the PopPK subset. We anticipate that approximately 80 patients will need to be enrolled in this subset collection in order to obtain sufficient samples for analysis.

Long term survival follow-up: OS for this treated population will be determined with every 3 month follow-up until either 240 deaths or 36 months, whichever occurs first, as observed from the time of randomization. The results for OS are expected to be reported March 2019. Exploratory evaluations: In addition, during Part 1 of the study, blood samples will be collected in all patients to assess the impact of soluble shed HER2/ECD on PK and efficacy at pre-dose on Cycles 1, 3, 5, 7, and end of treatment (EOT). Additional samples (ECD) will be obtained on Cycles 9, 13 and every 4 cycles thereafter, EOT and end of study (EOS) for continued evaluation of immunogenicity in patients continuing to receive therapy. A blood sample will be obtained on Cycle 1, Day 1, to be used for assay development and validation

Inclusion Criteria:

Locally recurrent or MBC that is not amenable to curative surgery and/or radiation.

Documentation of HER2 gene amplification by fluorescent in situ hybridization (FISH) (as defined by a ratio >2.0) or documentation of HER2-overexpression by immunohistochemistry (IHC) (defined as IHC3+, or IHC2+ with FISH confirmation) based on the sponsor-identified central laboratory prior to randomization. Archival tumor tissue samples can be used.

Pathologically confirmed breast cancer with at least one measurable metastatic target lesion (based on RECIST criteria, version 1.1). Bone, central nervous system (CNS), and skin lesions, as well as lesions that were irradiated, biopsied or had any form of local intervention or surgical manipulation are only to be assessed as non-target lesions.

Patients previously treated with trastuzumab or lapatinib in the adjuvant setting are allowed if metastatic disease was diagnosed at least one year after the last dose of treatment.

Prior treatment with hormonal agents or bisphosphonates/denosumab is allowed. Bisphosphonates/denosumab can be given simultaneously with study treatment but cannot start after randomization and is considered an indication of progressive disease (PD). Hormonal agents must be discontinued prior to beginning study therapy.

Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 - 2

• Serum creatinine ≤1.5 x ULN (upper limit of normal),
• Total bilirubin ≤1.0 x ULN (>1.0 x ULN if documented Gilbert's disease),
• Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) ≤2.5 x ULN,
• AST and/or ALT <1.5 x ULN if alkaline phosphatase >2.5 x ULN,
• Alkaline phosphatase >2.5 x ULN;if bone metastases present and no liver dysfunction present.

Left ventricular ejection fraction (LVEF) within institutional range of normal as measured by multiple gated acquisition scan or echocardiogram.

Exclusion Criteria:

Prior systemic therapy in the metastatic disease setting. This includes: chemotherapy, signal transduction inhibitors (e.g., lapatinib), HER2 targeted therapy (e.g., trastuzumab), or other investigational anticancer therapy.

Prior treatment with neoadjuvant or adjuvant anthracyclines with a cumulative dose of doxorubicin of >400 mg/m2, epirubicin dose >800 mg/m2.

Patients with bone or skin as the only site of disease. Patients with skin lesions measurable by CT scans or MRI as only site of measurable disease are allowed.

Surgery or radiotherapy ≤2 weeks preceding Day 1. Target lesions have to be outside the irradiated fields and the patient has fully recovered from surgery or radiotherapy.

Presence of unstable angina or a history of congestive heart failure according to the New York Heart Association criteria, history of myocardial infarction <1 year from randomization, clinically significant valvular disease, serious cardiac arrhythmia requiring treatment, uncontrolled hypertension or known pulmonary hypertension.

Peripheral sensory or motor neuropathy Grade 2 or higher according to the National Cancer Institute-Common Terminology Criteria (NCI-CTC) Version 4.03 [19].

Any other cancer, including contralateral breast cancer, within 5 years prior to screening with the exception of adequately treated ductal carcinoma in situ, adequately treated cervical carcinoma in situ, or adequately treated basal or squamous cell carcinoma of the skin.

Immunocompromized patients, including known seropositivity for human immunodeficiency virus, or current or chronic hepatitis B and/or hepatitis C infection (as detected by positive testing for hepatitis B surface antigen or antibody to hepatitis C virus with confirmatory testing).

Complete listing of Inc/Excl. within protocol