Onvansertib + Paclitaxel In TNBC

Inclusion Criteria: * Histologically confirmed invasive breast cancer with unresectable locally advanced or metastatic disease, included inflammatory breast cancer * Histologically or cytologically-confirmed triple negative breast cancer (defined as ER ≤ 10%, PR ≤ 10%, Her-2-neu negative per ASCO/CAP 2018 guidelines: 0-1+ by IHC or FISH-negative) * Concurrent endocrine therapy will not be allowed for patients with ER/PR ≥1% * Age ≥ 18 years * ECOG Performance Status of 0 or 1. * Subjects must be informed of the investigational nature of this study and must sign and give written informed consent in accordance with institutional and federal guidelines * Subject is not receiving any other cancer therapy. Subjects participating in surveys or observational studies are allowed. * Subjects with treated brain metastases that are stable on imaging for at least four weeks prior to registration and who are off steroid therapy are eligible. Subjects with small, asymptomatic incidental brain metastases that require no immediate treatment, including steroids, are also eligible. * For a male or a woman of child-bearing potential (WOCBP): Must agree to use contraception or take measures to avoid pregnancy during the study and for 180 days of the final dose of any study drug. * Adequate contraception is defined as follows: * Complete true abstinence. * Consistent and correct use of one of the following methods of birth control: * Male partner who is sterile prior to the female subjects entry into the study and is the sole sexual partner for that female patient. * Intrauterine device (IUD) with a documented failure rate of less than 1% per year. * WOCBP must have a negative serum or urine pregnancy test within 5 days prior to enrollment. \-- WOCBP include any female who has experienced menarche and who has not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation or bilateral oophorectomy) or is not postmenopausal (defined as amenorrhea \> 12 consecutive months); or women with documented serum follicle stimulating hormone (FSH) in postmenopausal level according to lab reference level. Even women who are using oral, implanted or injectable contraceptive hormones or mechanical products such as an IUD or barrier methods (diaphragm, condoms, spermicides) to prevent pregnancy or practicing abstinence or where partner is sterile (e.g., vasectomy), should be considered to be of child-bearing potential. * Must have acceptable organ function as detailed below: * leukocytes ≥3,000/mcL * absolute neutrophil count ≥1,500/mcL * platelets ≥100,000/mcL * hemoglobin ≥ 9.0 g/dL * total bilirubin ≤1.5 x institutional upper limit of normal (ULN) * AST(SGOT)/ALT(SGPT) ≤3 × institutional ULN * creatinine ≤1.5 ULN or creatinine clearance \> 50 ml/minute as calculated by the Cockcroft-Gault equation * Must have ability to understand and the willingness to sign a written informed consent form to provide blood sample(s) for specific correlative assays Exclusion Criteria: * Anti-cancer chemotherapy or biologic therapy administered within 21 days or 5 half-lives (whichever is shorter) prior to the first dose of study drug. * Palliative radiation therapy ≤ 2 weeks from enrollment. * \>3 lines of chemotherapy for metastatic disease in the phase 2 portion; no limit on prior lines in the dose escalation cohort. * Disease that has relapsed or progressed less than 6 months after most recent exposure to any taxane-based therapy in neoadjuvant, adjuvant, or metastatic setting. * Major surgery within 6 weeks prior to treatment initiation. * Women who are pregnant or breastfeeding. * Gastrointestinal (GI) disorder(s) that, in the opinion of the Investigator, would significantly impede the absorption of an oral agent (e.g., intestinal occlusion, active Crohn's disease, ulcerative colitis, extensive gastric and small intestine resection). * Unable or unwilling to swallow study drug. * Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, clinically significant non-healing or healing wounds, symptomatic congestive heart failure (CHF) Class II or higher according to the New York Heart Association (NYHA) Functional Classification), unstable angina pectoris, clinically significant cardiac arrhythmia, significant pulmonary disease (shortness of breath at rest or mild exertion), uncontrolled infection or psychiatric illness/social situations that would limit compliance with study requirements. * Known active infection with COVID-19 or Human Immunodeficiency Virus (HIV), with measurable viral titer, and/or active infection with hepatitis B or C (subjects who have had a hepatitis B virus (HBV) immunization are eligible; subjects with HIV and CD4+ T-cell (CD4+) counts ≥ 350 cells/uL are eligible; subjects on established ART for at least four weeks and have an HIV viral load less than 400 copies/mL prior to enrollment are eligible). * Clinically significant ascites or pleural effusions. * Known hypersensitivity to paclitaxel. * Grade 2 or higher peripheral neuropathy. * Subjects with a history of other malignancies except: adequately treated non-melanoma skin cancer, curatively treated in-situ cancer of the cervix, or other solid tumors curatively treated with no evidence of disease for \> 2 years. * Any active disease condition that would render the protocol treatment dangerous or impair the ability of the patient to receive study drug. * QT interval with Fridericia's correction (QTcF) \> 480 milliseconds (Vandenberk 2016). The QTcF should be calculated as the arithmetic mean of the QTcF on triplicate ECGs. In the case of potentially correctible causes of QT prolongation, (e.g., medications, hypokalemia), the triplicate ECG may be repeated once during Screening and that result may be used to determine eligibility. * Planned concomitant use of medications known to prolong the QT/QTc interval. * Presence of risk factors for torsade de pointes, including family history of Long QT Syndrome or uncorrected hypokalemia * Strong inhibitors/inducers of CYP3A4 are prohibited