Inclusion Criteria:

• Pathologically confirmed diagnosis of breast cancer with radiographic evidence of incurable, unresectable, locally advanced or metastatic disease.
• One of the following disease subtypes and prior therapies:
  • Part A: Patients with TN disease (ER/PR/HER2-negative) must have received at least 2 prior cytotoxic regimens in the incurable, unresectable LA/MBC setting.
  • Part A: Patients with ER-positive and/or PR-positive/HER2-negative disease must have received at least 2 prior cytotoxic regimens in the incurable, unresectable LA/MBC setting, and are no longer a candidate for hormonal therapy as documented in the medical record.
  • Part B: Patients with HER2-positive disease must have received at least 2 prior cytotoxic regimens in the incurable, unresectable LA/MBC setting. HER2-positivity will be determined by the local laboratory.
  • Part C: Patients with TN disease who have received up to 4 prior regimens, and at least 2 must have been given for incurable, unresectable LA/MBC.
    • One or 2 of these regimens may have been administered as adjuvant and/or neoadjuvant therapy, but at least 2 must have been given for incurable, unresectable LA/MBC.
    • Treatment with agents other than hormonally directed/endocrine therapies will be counted as regimens.
  • Part D: Patients with TN disease who have received one prior cytotoxic regimen for incurable, unresectable LA/MBC.
  • Part E: Patients with ER-positive and/or PR-positive/HER2-negative disease who are chemotherapy-eligible, have progressed on or relapsed after receiving endocrine or hormonally-directly therapy with CDK inhibitors, have received no more than one prior cytotoxic regimen in the incurable, unresectable LA/MBC setting, and are no longer a candidate for hormonal therapy as documented in the medical record.
    • Patients will be considered ER-positive and/or PR-positive if biopsies show greater than 1% expression of ER or PR.
    • Patients will be deemed HER2-negative if they meet the ASCO/CAP 2013 guideline recommendations for HER2-negative status.
• Newly obtained tumor tissue biopsy must be collected for central pathology determination of LIV-1 expression. Archived tumor tissue, if available, is required for LIV-1 expression analysis. If a patient has lesions that cannot be safely and/or adequately sampled, the medical monitor may allow for an exemption to this requirement.
• Measureable disease as defined in RECIST Version 1.1: at least 1 tumor lesion ≥10 mm in the longest diameter or a lymph node ≥15 mm in short axis measurement assessed by CT (computed tomography) scan.
• Females ≥ 18 years of age.
• An Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1.
• Patients must have completed treatment with chemotherapy, radiotherapy, hormonal therapy, or other treatment with an investigational agent ≥2 weeks prior to first dose of study drug, unless disease progression is documented, and have recovered from any clinically significant toxicity associated with the treatment.
• Patients must have completed treatment with a biologic agent or immunotherapy ≥4 weeks prior to the first dose of study drug, unless disease progression is documented, and have recovered from any clinically significant toxicity associated with the treatment. An exception to this requirement is treatment with denosumab, which is permitted on study.
• The following baseline laboratory data:
  • absolute neutrophil count (ANC) ≥500/μL;
  • platelet count ≥00,000/μL;
  • hemoglobin (Hgb) ≥.0 g/dL;
  • serum bilirubin ≤.5x upper limit of normal (ULN);
  • serum creatinine ≤.5x ULN;
  • alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤.5x ULN or ≤x ULN if liver metastases present .
• Females of childbearing potential must have a negative serum or urine beta human chorionic gonadotrophin (β-hCG) pregnancy test result within 7 days prior to the first dose of SGN-LIV1A and must agree to use 2 effective contraceptive methods during the study and for an extended time after the last dose of study drug (Parts A and C: 6 months following the last dose of SGN-LIV1A and Part B: 7 months following the last dose of combination therapy with SGN-LIV1A and trastuzumab). Examples of effective contraception methods include, but are not limited to, the following: non-hormonal intrauterine device (IUD), condoms, diaphragm, tubal ligation (injections, implants), barrier methods, vasectomy (for male partners), or complete abstinence. Barrier methods include male and female condoms, diaphragms, and spermicides (creams or gels that contain a chemical to kill sperm).
• Patients must provide written informed consent.
• Part B only: Left ventricular ejection fraction (LVEF) ≥0% as determined by echocardiogram or multigated acquisition (MUGA) scan.

Exclusion Criteria:

• Pre-existing neuropathy of ≥ Grade 2.
• History of another primary invasive malignancy that has not been in remission for at least 3 years with the exception of carcinoma in situ of the cervix, squamous or basal cell skin cancer, or thyroid cancer.
• Cerebral/meningeal disease that is related to the underlying malignancy and has not been definitively treated.
• Any active Grade 3 or higher (per the NCI CTCAE v4.03) viral, bacterial, or fungal infection within 2 weeks prior to the first dose of SGN-LIV1A.
• Positive for hepatitis B by surface antigen expression, active hepatitis C infection (positive by polymerase chain reaction (PCR) or on antiviral therapy for hepatitis C within the last 6 months), or a known history of being seropositive for HIV.
• Documented history of a cerebral vascular event (stroke or transient ischemic attack), unstable angina, myocardial infarction, or cardiac symptoms (including congestive heart failure) consistent with New York Heart Association Class III-IV within 6 months prior to their first dose of SGN-LIV1A).
• Females who are breastfeeding.
• Known hypersensitivity to any excipient contained in the drug formulation of SGN-LIV1A.
• Major surgery ≤3 weeks of study treatment.
• Part B only: Known hypersensitivity to trastuzumab.
• Prior treatment with SGN-LIV1A or prior treatment with an MMAE-containing therapy.