Rebastinib Plus Antitubulin Therapy With Paclitaxel or Eribulin in Metastatic Breast Cancer
Rebastinib Plus Antitubulin Therapy With Paclitaxel or Eribulin in Metastatic Breast Cancer
The purpose of this study is to determine the safety and tolerability of rebastinib when
 combined with antitubulin therapy with paclitaxel or eribulin in patients with advanced
 breast cancer.
Metastasis is the primary cause of death from breast cancer, invasive carcinoma cells in
 mouse and rat mammary tumors co-migrate accompanied by macrophages towards intravasation
 sites . The intravasation occurs at sites where a TIE2-expressing macrophage, a
 mena-expressing tumor cell, and an endothelial cell are in direct contact, forming a
 micro-anatomic structure called tumor micro-environment of metastasis (TMEM). Ablation of the
 presence or activity of the TMEM associated macrophages blocks intravasation at TMEM
 demonstrating an essential role of perivascular macrophages in TMEM function. Rebastinib, a
 TIE2 inhibitor , blocks TMEM assembly and function in-vivo and in-vitro assays. We
 hypothesize that rebastinib combined with antitubulin therapy (eribulin or paclitaxel) could
 improve clinical outcomes in breast cancer by preventing intravasation at TMEM sites and
 preventing further metastasis.
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