Inclusion Criteria:

• Histologically confirmed breast adenocarcinoma that is metastatic. Receptor status of the tumor must be known.
• Disease progression during or after immediate previous therapy, or intolerable toxicity leading to cessation of immediate previous therapy

• Previous treatment for MBC:

  • AT Cohort: Prior AT required as adjuvant or metastatic therapy; no more than 2 prior chemotherapy regimens for MBC.
  • ATX Cohort: Prior ATX required as adjuvant or metastatic therapy;no more than 4 prior chemotherapy regimens for MBC.

• For patients with positive receptor status:

  • Patients with HER2+ MBC must have received prior trastuzumab.
  • Patients with ER+ MBC must have received prior hormone therapy.
• Measurable disease by RECIST Version 1.1
• Women 18 years or older
• ECOG performance status of 0 to 2
• Adequate bone marrow, renal and hepatic functions

Exclusion Criteria:

• Major surgery within 3 weeks before study start
• Known or suspected brain metastases requiring intervention with steroids and/or radiation therapy
• Prior chemotherapy, immunotherapy, non-investigational agent, or other therapy used to treat the cancer within 3 weeks before scheduled administration of EZN-2208

• History of other primary cancer within 5 years of enrollment, unless

  1. Curatively resected non-melanomatous skin cancer, or
  2. Curatively resected cervical cancer
• Lack of recovery to Grade 1 from any reversible side effects related to the administration of an investigational agent, chemotherapy, or other prior treatments for the cancer
• Current participation in another clinical study with an investigational agent and/or use of an investigational drug (not including investigational use of an approved drug) in the 30 days before the first administration of EZN-2208
• Known chronic infectious disease, such as AIDS