Rebastinib Tosylate and Paclitaxel or Eribuilin Mesylate in Treating Patients with HER2 Negative Metastatic Breast Cancer

Inclusion Criteria

• Histologically confirmed adenocarcinoma of the breast that is Her2 negative (by DAKO Herceptest, fluorescence in situ hybridization [FISH], or other approved assay)
• Metastatic breast cancer not amenable to potentially curative surgery; patients must have disease that is measurable and/or non-measurable as defined by RECIST 1.1 criteria (assessed by computed tomography [CT] scan chest/abdomen/pelvis with contrast or fludeoxyglucose [FDG] positron emission tomography [PET]-CT scan obtained within 4 weeks of registration)
• Prior therapy * Arm A: Rebastinib plus paclitaxel: up to two prior non-taxane chemotherapy regimens for metastatic or incurable locally advanced disease permitted (no prior paclitaxel or eribulin); patients with estrogen receptor (ER)-positive disease are required to have relapse or progression on at least one line of endocrine therapy * Arm B: Rebastinib plus eribulin: up to three prior chemotherapy regimens for metastatic or incurable locally advanced disease permitted (no prior eribulin, but prior paclitaxel allowed): patients with ER-positive disease are required to have relapse or progression on at least one line of endocrine therapy
• Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
• Leukocytes >= 3,000/uL
• Absolute neutrophil count >= 1,500/uL
• Platelets >= 100,00/uL
• Hemoglobin > 9 g/dL
• Total bilirubin within normal institutional limits
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) =< 2.5 X institutional upper limit of normal
• Creatinine within normal institutional limits
• Left ventricular ejection fraction at or above institutional lower limits of normal (by echocardiogram within 12 weeks of registration)
• Electrocardiogram (EKG) corrected QT interval (QTc) < 450 msec (females)
• Serum calcium & phosphorus within normal institutional limits
• Glucose within normal institutional limits
• Negative urine or serum beta-human chorionic gonadotropin (BHCG) for women of childbearing potential only (within 7 days of registration)
• No prior known history of retinal neovascularization, macular edema or macular degeneration; patients without such a history are required to have a baseline ophthalmologic exam as part of screening, and must not have evidence of retinal neovascularization, macular edema or macular degeneration on the screening exam in order to be eligible
• Patients must be disease-free of prior invasive malignancies for >= 2 years with the exception of curatively-treated basal cell or squamous cell carcinoma of the skin, carcinoma in situ of the cervix; patient with the following prior concurrent diagnoses are eligible: lobular carcinoma in situ, contralateral ductal carcinoma in situ, or contralateral invasive ductal and/or lobular carcinoma
• Women of child-bearing potential must not be pregnant or breast feeding; they must also agree to use adequate contraception (hormonal or barrier method of birth control) and not be breast feeding prior to study entry, for the duration of study participation, and for up to 30 days after completion of all protocol therapy; should a woman become pregnant or suspect she is pregnant while participating in this study or up to 30 days after completion of protocol therapy, she should inform her treating physician immediately
• Ability to understand and the willingness to sign a written informed consent document
• At least 30 days from major surgery before study enrollment, with full recovery
• Concomitant therapy with bisphosphonates, RANKL inhibitors or growth-colony-stimulating factors (G-CSF) is allowed as per physician decision
• Patients for the expansion cohort must have a CTC (TelomeScan) drawn in the screening phase if other eligibility criteria are met, and must be CTC-positive in order to be eligible for enrollment in the expansion cohort

Exclusion Criteria

• History of allergic reactions attributed to compounds of similar chemical or biological composition to rebastinib or other agents used in the study (e.g., Cremophor)
• History of cardiac disease, including: (a) myocardial infarction within 6 months of the start of study, (b) history of QTc prolongation or QTc >= 450 msec on screening EKG, history of additional risk factors for torsade de pointes (e.g., heart failure, hyperkalemia), and family history of long QT syndrome; (c) use of concomitant drugs that prolong QT/QTc interval; (d) New York Heart Association class III or IV heart disease, (e), active ischemia or any other uncontrolled cardiac condition such as angina pectoris, clinically signification cardiac arrhythmia requiring therapy
• Intercurrent illness that would substantially increase the risk of treatment associated complications (e.g., active infection, uncontrolled diabetes mellitus or hypertension) and/or psychiatric illness/social situations that would interfere with the patient's ability to comply with the treatment regimen
• Patients with human immunodeficiency virus (HIV) infection are excluded from the study
• Patients with untreated brain metastasis are excluded; patients with a prior history of brain metastasis are eligible if they have received prior brain radiation, have improved or stable intracranial disease for at least 3 months after completion of last course of radiation, and are not taking corticosteroids for treatment of brain metastasis; patients with a prior history of brain metastases who meet other eligibility criteria
• Treatment with other chemotherapy regimen within the past 2 weeks
• Treatment with trastuzumab, bevacizumab or other targeted therapies within the past 4 weeks