This phase II trial studies how well tivantinib works in treating patients with recurrent or metastatic breast cancer. Tivantinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

PRIMARY OBJECTIVES:

I. To evaluate the activity of tivantinib (ARQ-197) as defined by 6-month progression-free survival (PFS) of participants with triple-negative metastatic breast cancer.

SECONDARY OBJECTIVES:

I. To evaluate objective response based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria.

II. To evaluate c-Met and phospho c-Met expression in archival tumor tissue. (Exploratory) III. To evaluate the incidence of c-Met-positive circulating tumor cells at baseline. (Exploratory) IV. To evaluate the effect of ARQ-197 on serum markers relevant to c-Met pathway (hepatocyte growth factor [HGF] and vascular endothelial growth factor [VEGF]). (Exploratory) V. To evaluate phosphatase and tensin homolog (PTEN) loss and PI3K mutations in archival tumor tissue. (Exploratory) VI. To evaluate proportion of participants with basal-like breast cancer. (Exploratory)

OUTLINE: This is a multicenter study.

Patients receive tivantinib orally (PO) twice daily (BID) on days 1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients undergo blood sample collection at baseline and periodically during study for c-Met expression, relevant markers (HGF and VEGF), PTEN loss, and PI3K mutation analysis by fluorescent in situ hybridization (FISH) and immunohistochemistry (IHC). Archived tumor tissue samples are also analyzed.

After completion of study treatment, patients are followed up every 6 months.

Inclusion Criteria:

• Participants must have histologically or cytologically confirmed invasive breast cancer, with recurrent or metastatic disease; participants without pathologic or cytologic confirmation of metastatic disease should have unequivocal evidence of metastasis from physical examination or radiologic evaluation

• Participants must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as >= 20 mm with conventional techniques or as >= 10 mm with spiral computed tomography (CT) scan

• Participants must have recent evidence of progressive disease

  • Participants must have received 1-3 prior chemotherapeutic regimens for metastatic breast cancer and must have been off treatment with chemotherapy for at least 14 days before enrollment in the study

• Participants must have discontinued all biologic therapy (including vaccines) at least 14 days before enrollment in the study

• Participants must have discontinued any investigational therapy at least 14 days before enrollment in the study

• Participants may have received prior radiation therapy in either the metastatic or early-stage setting

  • Radiation therapy must be completed at least 14 days before enrollment in the study
  • Participant must not have received radiation to > 25% of his or her bone marrow within 30 days of starting study treatment

• Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)

• Hemoglobin >= 9.0 g/dL

• Absolute neutrophil count >= 1,500/mcL

• Platelets >= 100,000/mcL

• Total bilirubin =< 1.5 times upper limit of normal (ULN)

• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamic pyruvate transaminase [SGPT]) =< 2.5 times institutional ULN; for participants with documented liver metastases, AST/ALT =< 5.0 times ULN

• Serum creatinine =< 1.5 times ULN OR creatinine clearance >= 60 mL/min/1.73 m^2 for participants with creatinine levels above institutional normal

• Either the primary tumor and/or the metastasis must be triple-negative; the invasive tumor must be hormone-receptor poor, defined as estrogen-receptor negative (ER-) and progesterone-receptor negative (PR-), or staining < 10% by immunohistochemistry (IHC)

  • Human epidermal growth factor receptor 2 (HER2) status: the invasive tumor must be HER2-negative, defined as 0 or 1+ by IHC, or FISH < 2.0

• Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) during the study and for 90 days after the last investigational drug dose received

• Female subjects of childbearing potential must have a negative serum pregnancy test within 21 days of cycle 1 day 1

• Participants on bisphosphonates may continue receiving bisphosphonate therapy during study treatment; bisphosphonate therapy may also be initiated on study treatment if needed

• Confirmed availability of formalin-fixed, paraffin-embedded (FFPE) tumor tissue

• Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

• Participants who have received chemotherapy, biologic, investigational, or radiotherapy within 14 days prior to entering the study

• Participants who are receiving any other investigational agents

• Known brain metastases that are untreated, symptomatic, or require therapy to control symptoms

  • Participants with a history of treated central nervous system (CNS) metastases are eligible

    • Treated brain metastases are defined as those having no evidence of progression or hemorrhage for >= 2 months after treatment, and no ongoing requirement for corticosteroids, as ascertained by clinical examination and brain imaging (magnetic resonance imaging or computed tomography [CT] scan) during the screening period
    • Treatment for brain metastases may include whole-brain radiotherapy, radiosurgery, or a combination as deemed appropriate by the treating physician

  • Participants may be taking anti-convulsant medications, which must be non-enzyme-inducing anti-epileptic drugs

• History of allergic reactions attributed to compounds of similar chemical or biologic composition to ARQ 197

• History of congestive heart failure defined as Class II to IV per New York Heart Association (NYHA) classification; active coronary artery disease (CAD); clinically significant bradycardia or other uncontrolled, cardiac arrhythmia defined as >= grade 3 according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 4.0, or uncontrolled hypertension; myocardial infarction occurring within 6 months prior to study entry (myocardial infarction occurring > 6 months prior to study entry is permitted)

• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements

• Pregnant women are excluded from this study

• Human immunodeficiency virus (HIV)-positive participants on combination antiretroviral therapy are ineligible