Study of Cirmtuzumab and Paclitaxel for Metastatic or Locally Advanced, Unresectable Breast Cancer

INCLUSION CRITERIA: * Biopsy-confirmed, metastatic or locally advanced surgically unresectable, HER2 negative breast cancer. HER2 status should reflect the most recent biopsy results. Note: HER2 negative breast cancer is defined according to the American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines 2013 for HER2 testing performed in a CLIA-certified laboratory. * ER/PR negative (\<10% of cells staining for ER or PR) breast cancer or have ER/PR positive (≥10% of cells staining for ER or PR) breast cancer that has exhausted standard endocrine therapy and/or in the opinion of the treating oncologist, warrants cytotoxic chemotherapy. * Measurable disease as defined by RECIST v1.1. Measurable lesions will be confirmed by radiographic imaging (CT or MRI). Patients with bone only disease will be eligible if disease is considered measurable and a soft tissue component is present and can be biopsied.. * There is no limit to prior lines of therapy, but patients must not have received prior taxane chemotherapy in the metastatic setting. * ECOG Performance Status ≤ 2. * Adequate organ function as defined below: * Absolute Neutrophil Count ≥ 1.0 x 10\^9/L * Platelet count ≥ 100,000 /μL * Hemoglobin ≥ 8.0 g/dL * Total bilirubin ≤ 1.5 x upper limit of normal * AST and ALT ≤ 3 x upper limit of normal * Serum creatinine ≤ 2 x upper limit of normal OR Creatinine clearance \> 40 ml/min/1.73 m\^2 * Women of child-bearing potential and male subjects who are sexually active with a woman of childbearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for at least 6 months following last infusion of cirmtuzumab. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately. * Existing neuropathy must be no greater than Grade 1. * No concurrent antibody therapy can be planned with the exception of denosumab for use in bone metastasis. * CNS metastases are allowed as long as the metastases are asymptomatic, have been treated with radiation, and have been stable for \> 6 weeks off steroids. EXCLUSION CRITERIA: * Patient is currently receiving chemotherapy or has received another chemotherapy within 5 half-lives, radiotherapy or immunotherapy within 2 weeks prior to study treatment initiation. * Patient has known, untreated and/or symptomatic central nervous system (CNS) metastases and/or carcinomatous meningitis. * Patient had disease that was refractory to paclitaxel in the neoadjuvant setting and/or developed metastatic breast cancer within 6 months of neoadjuvant or adjuvant taxane chemotherapy. * Patient has had major surgery within 3 weeks prior to enrollment. * Patient has severe and/or uncontrolled medical disease(s) (i.e., myocardial infarction within 6 months of study, CKD stage IV or above, severe chronic pulmonary disease or active infection). * The patient has known acute or chronic hepatitis B or C. * The patient has a history of allergic reactions attributed to compounds of similar chemical or biologic composition to paclitaxel. * The patient has a history of another malignancy within 2 years prior to study entry, except curatively treated non-melanotic skin cancer, cervical carcinoma in situ or stage I colon cancer. * Patient has a history of non-compliance or other medical illness that would preclude compliance with study procedures. * Patient has a known diagnosis of human immunodeficiency virus (HIV) infection. * Patient has severe cardiac insufficiency (NYHA III or IV) with uncontrolled and/or unstable cardiac or coronary artery disease * Patient is pregnant or nursing. There is a potential for congenital abnormalities and for this regimen to harm nursing infants.