Rebastinib Plus Antitubulin Therapy With Paclitaxel or Eribulin in Metastatic Breast Cancer

Inclusion Criteria:

1. Histologically confirmed adenocarcinoma of the breast that is HER2 (human epidermal growth factor receptor 2) negative; based on ASCO(american society of clinical oncology)/ CAP (college of American Pathologists) guidelines as: (a) IHC (immuno-histochemistry) 1+ negative or IHC 0 negative; or (b) ISH (in situ hybridization ) negative using single probe ISH( average HER2 copy number \< 4.0 signals/cell), or dual probe ISH ( HER2/CEP17 ratio \<2.0, average HER2 copy number \<4.0 signals/cell)
2. 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
3. Prior chemotherapy and/or endocrine therapy. Patients will be assigned to arm A or arm B depending on their prior exposure to paclitaxel and eribulin.

   * Arm A: Rebastinib plus paclitaxel: Up to two prior non-taxane chemotherapy regimens for metastatic or incurable locally advanced disease permitted (no prior paclitaxel, docetaxel, or eribulin for metastatic disease)..Prior therapy with paclitaxel or docetaxel in the neo/adjuvant setting is allowable if there is at least a 6 month interval between the last adjuvant/neoadjuvant paclitaxel or docetaxel dose and recurrence.
   * Arm B: Rebastinib plus Eribulin: Patients must have previously received at least two chemotherapeutic regimens for the treatment of metastatic disease (no prior eribulin, but prior paclitaxel, nab-paclitaxel, or docetaxel allowed). Prior therapy should have included a taxane in either the adjuvant or metastatic setting.
   * Arms A and B: Patients with hormone receptor positive disease must have had progressive disease and at least 2 lines of endocrine therapy, including one endocrine regimen used in combination with an approved CDK 4/6 (cyclin-dependent kinase ) inhibitor (eg, palbociclib). Relapse while receiving or within 6 months of completing adjuvant endocrine therapy may be considered failure of one prior endocrine regimen
4. Female and age \>18 years. Because breast carcinoma is a disease of adults that rarely occurs in children, children are excluded from this study. In addition, the safety of rebastinib in pediatric patients has not been evaluated.
5. ECOG (Eastern Cooperative Oncology Group) performance status 0 or 1.
6. Normal organ and marrow function as defined below within 2 weeks of registration (except where specified otherwise):

   Leukocytes \>3,000/µL ; Absolute neutrophil count \>1,500/µL ; Platelets \>100,000/ µL Hemoglobin \> 9 g/dL ; Total bilirubin (within normal institutional limits) AST (aspartate aminotransferase)/ALT (alanine aminotransferase) \<2.5 X institutional upper limit of normal ; Creatinine (within normal institutional limits) ; EKG QTc \< 450 msec (females)

   Left ventricular ejection fraction at or above institutional lower limits of normal (by echocardiogram within 12 weeks of registration) ; Glucose (within normal limits) Serum calcium \& phosphorus (within normal institutional limits); Negative urine or serum B-HCG(Beta-Human Chorionic Gonadotropin)
7. No significant ocular disease: 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.
8. No other active cancer: 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 or concurrent diagnoses are eligible: lobular carcinoma in situ, contralateral ductal carcinoma in situ, or contralateral invasive ductal and/or lobular carcinoma.
9. 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.
10. Ability to understand and the willingness to sign a written informed consent document.
11. At least 30 days from major surgery before study enrollment, with full recovery.
12. Concomitant therapy with bisphosphonates, RANKL inhibitors or growth-colony-stimulating factor (G-CSF) is allowed as per physician decision.
13. Expansion cohort: 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:

1. History of allergic reactions attributed to compounds of similar chemical or biologic composition to Rebastinib or other agents used in the study (e.g., Cremophor)
2. History of cardiac disease, including: (a) myocardial infarction within 6 months of the start of study, (b) history of QTc(corrected QT interval ) 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.(see "Study reference manual" for further details) (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 significant cardiac arrhythmia requiring therapy.
3. bIntercurrent 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.
4. Patients with HIV infection are excluded from the study because of possible pharmacokinetic interactions with Rebastinib and antiretroviral therapy.
5. 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
6. Treatment with other chemotherapy regimen within the past 2 weeks.
7. Treatment with trastuzumab, bevacizumab or other targeted therapies within the past 4 weeks.
8. Patients who have not recovered (i.e., CTCAE Grade ≤1 or baseline) from an adverse event due to a previously administered agent, excluding alopecia.
9. Patients with Grade \>1 neuropathy
10. Patients with uncontrolled hypertension (defined as systolic blood pressure \> 150 and/or diastolic blood pressure \> 90 mm/mg).
11. Patients that have a malabsorption syndrome or other illness which could affect oral absorption