A Multinational, Multicenter, Randomized, Phase 3 Study of Tesetaxel Plus a Reduced Dose of Capecitabine Versus Capecitabine Alone in Patients With HER2 Negative, HR Positive, Locally Advanced or Metastatic Breast Cancer Previously Treated With a Taxane

• Female or male patients at least 18 years of age

• Histologically or cytologically confirmed breast cancer

• 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

• 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

• 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

• Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, or 2

• Prior therapy (at least one completed dose) with a taxane-containing regimen in the neoadjuvant or adjuvant setting

• Prior therapy with an anthracycline-containing regimen in the neoadjuvant, adjuvant, or metastatic setting, where indicated by local regulation or Investigator judgment.

• 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.

⁃ 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.

⁃ 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

⁃ 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

⁃ Ability to swallow an oral solid-dosage form of medication

⁃ 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)

⁃ 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

⁃ 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

⁃ Written informed consent and authorization to use and disclose health information

⁃ Ability to comprehend and comply with the requirements of the study