Tesetaxel Plus Reduced Dose of Capecitabine vs. Capecitabine in HER2 Negative, HR Positive, LA/MBC

Inclusion Criteria:

1. Female or male patients at least 18 years of age
2. Histologically or cytologically confirmed breast cancer
3. HER2 negative disease based on local testing: American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) guidelines should be utilized for assessing HER2 status
4. HR (estrogen receptor \[ER\] and/or progesterone receptor \[PgR\]) positive disease based on local testing: ASCO/CAP guidelines should be utilized for assessing HR status
5. Measurable disease per RECIST 1.1 or bone-only disease with lytic component

   * Patients with bone-only metastatic cancer must have a lytic or mixed lytic-blastic lesion that can be accurately assessed by computerized tomography (CT) or magnetic resonance imaging (MRI). Patients with bone-only disease without a lytic component (ie, blastic-only metastasis) are not eligible.
   * Known metastases to the CNS are permitted but not required. The following criteria apply:

     * Patients must be neurologically stable and either off corticosteroids or currently treated with a maximum daily dose of 4 mg of dexamethasone (or equivalent), with no increase in corticosteroid dose within 7 days prior to randomization
     * Patients with a history of CNS metastases but with no current evidence of CNS lesions following local therapy are eligible
     * Patients may have CNS metastases that are stable or progressing radiologically
     * Patients with current evidence of leptomeningeal disease are not eligible
     * Patients may have untreated brain metastases or previously treated brain metastases, as long as no immediate local CNS-directed therapy is indicated
     * Any prior whole brain radiation therapy must have been completed \> 14 days prior to the date of randomization
     * Prior stereotactic brain radiosurgery is permitted
     * CNS surgical resection must have been completed \> 28 days prior to the date of randomization; patient must have complete recovery from surgery
6. Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, or 2
7. Prior therapy (at least one completed dose) with a taxane-containing regimen in the neoadjuvant or adjuvant setting
8. Prior therapy with an anthracycline-containing regimen in the neoadjuvant, adjuvant, or metastatic setting, where indicated by local regulation or Investigator judgment.
9. Prior endocrine therapy with or without a CDK 4/6 inhibitor unless endocrine therapy is not indicated (ie, short relapse-free interval while on adjuvant endocrine therapy \[endocrine resistance\]; rapidly progressing disease/visceral crisis; or endocrine intolerance). Any targeted therapies approved for HER2 negative, HR positive LA/MBC, including everolimus, are permitted as prior therapy. There is no limit to the number of prior endocrine therapies.
10. Documented disease recurrence or disease progression of: (a) locally advanced disease that is not considered curable by surgery and/or radiation; or (b) metastatic disease.
11. Adequate hematologic, hepatic and renal function, as evidenced by:

    * Absolute neutrophil count (ANC) ≥ 1,500/μL without colony-stimulating factor support
    * Platelet count ≥ 100,000/μL
    * Hemoglobin ≥ 10 g/dL without need for hematopoietic growth factor or transfusion support
    * Total bilirubin \< 1.5 × upper limit of normal (ULN); does not apply to patients with Gilbert's syndrome
    * Alanine aminotransferase (ALT) \< 3 × ULN unless hepatic metastases are present, then \< 5 × ULN
    * Aspartate aminotransferase (AST) \< 3 × ULN unless hepatic metastases are present, then \< 5 × ULN
    * Alkaline phosphatase \< 2.5 × ULN unless hepatic metastases are present, then \< 5 × ULN
    * Calculated creatinine clearance ≥ 50 mL/min (by Cockcroft-Gault formula or local standard)
    * Serum albumin ≥ 3.0 g/dL
    * Prothrombin time (PT) \< 1.5 × ULN or international normalized ratio (INR) \< 1.3, and partial thromboplastin time (PTT) \< 1.5 × ULN, unless the patient is on a therapeutic anticoagulant
12. Complete recovery to baseline or Grade 1 per National Cancer Institute (NCI) CTCAE version 5.0 from adverse effects of prior surgery, radiotherapy, endocrine therapy and other therapy, as applicable, with the exception of Grade 2 alopecia from prior chemotherapy
13. Ability to swallow an oral solid-dosage form of medication
14. A negative serum pregnancy test within 7 days prior to the first dose of Study treatment in women of childbearing potential (ie, all women except those who are post menopause for ≥ 1 year or who have a history of hysterectomy or surgical sterilization)
15. Women of childbearing potential must use an effective, non-hormonal form of contraception from Screening throughout the Treatment Phase and until 70 days after the last dose of study treatment

    • Acceptable methods include: copper intrauterine devices or double barrier methods, including male/female condoms with spermicide and use of contraceptive sponge, cervical cap, or diaphragm
16. Male patients must use an effective, non-hormonal form of contraception from screening throughout the treatment phase and until 130 days after last dose of study treatment

    • Acceptable methods include male/female condoms with spermicide, or vasectomy with medical confirmation of surgical success
17. Written informed consent and authorization to use and disclose health information
18. Ability to comprehend and comply with the requirements of the study

Exclusion Criteria:

1. Two or more prior chemotherapy regimens for advanced disease
2. Prior treatment with a taxane in the metastatic setting
3. Prior treatment with capecitabine at any dose
4. Current evidence of leptomeningeal disease
5. Other cancer that required therapy within the preceding 5 years other than adequately treated: (a) non-melanoma skin cancer or in situ cancer; or (b) following approval by the Medical Monitor, other cancer that has a very low risk of interfering with the safety or efficacy endpoints of the study
6. Known human immunodeficiency virus infection, unless well controlled. Patients who are on an adequate antiviral regimen with no evidence of active infection are considered well controlled.
7. Active hepatitis B or active hepatitis C infection
8. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the Investigator, would make the patient inappropriate for entry into this study
9. Presence of neuropathy \> Grade 1 per NCI CTCAE version 5.0
10. History of hypersensitivity to taxanes; hypersensitivity to the solvent does not preclude patient participation in this study
11. Anticancer treatment, including endocrine therapy, radiotherapy (except stereotactic brain radiosurgery), chemotherapy, biologic therapy, or therapy in an investigational clinical study, ≤ 14 days prior to the date of randomization
12. Major surgery ≤ 28 days prior to the date of randomization; patient must have complete recovery from surgery
13. Less than 2 weeks or 5 plasma half-lives (whichever is greater) since last use of a medication or ingestion of an agent, beverage or food that is a known clinically relevant strong inhibitor or known clinically relevant inducer of the cytochrome P450 (CYP) 3A pathway (patients should discontinue taking any regularly taken medication that is a strong inhibitor or inducer of the CYP3A pathway)
14. History of hypersensitivity or unexpected reactions to capecitabine, other fluoropyrimidine agents or any of their ingredients
15. Known dihydropyrimidine dehydrogenase (DPD) deficiency. Testing for DPD deficiency must be performed where required by local regulations, using a validated method that is approved by local health authorities.
16. Pregnant or breastfeeding
17. If, in the opinion of the Investigator, the patient is deemed unwilling or unable to comply with the requirements of the study
18. Treatment with brivudine, sorivudine or its chemically-related analogs ≤ 28 days prior to the date of randomization