HER2 Negative, Hormone Receptor Positive, Locally Advanced or Metastatic Breast Cancer

Primary Objective The primary objective is to establish the efficacy of tesetaxel plus a reduced dose of capecitabine in patients with HER2 negative, HR positive LA/MBC not previously treated with a taxane in the neoadjuvant, adjuvant, or metastatic setting. Secondary Objectives The secondary objectives are to assess the safety and tolerability of tesetaxel plus a reduced dose of capecitabine in patients with HER2 negative, HR positive LA/MBC not previously treated with a taxane in the neoadjuvant, adjuvant, or metastatic setting. Pharmacokinetic Objectives The pharmacokinetic objectives are to:  Investigate the relationship between the PK of tesetaxel and efficacy and safety endpoints in patients with HER2 negative, HR positive LA/MBC not previously treated with a taxane in the neoadjuvant, adjuvant, or metastatic setting; and  Investigate the potential for a PK drug-drug interaction of tesetaxel on capecitabine and its active metabolite, 5-FU.

Tesetaxel

Tesetaxel

capsule

5, 20

Primary Outcome Measures :
ORR as assessed by the IRC [ Time Frame: Approximately 2.0-2.5 years ]

Secondary Outcome Measures :
DoR as assessed by the IRC [ Time Frame: Approximately 2.0-2.5 years ]
PFS as assessed by the IRC [ Time Frame: Approximately 2.0-2.5 years ]
DCR as assessed by the IRC [ Time Frame: Approximately 2.0-2.5 years ]
OS [ Time Frame: Approximately 3.0-3.5 years ]
Central nervous system (CNS) ORR as assessed by the CNS IRC in patients with CNS metastases at baseline [ Time Frame: Approximately 2.0-2.5 years ]
CNS DoR as assessed by the CNS IRC in patients with CNS metastases at baseline [ Time Frame: Approximately 2.0-2.5 years ]
CNS PFS as assessed by the CNS IRC in patients with CNS metastases at baseline or a history of CNS metastases and in the intent-to-treat (ITT) population [ Time Frame: Approximately 2.0-2.5 years ]
CNS OS in patients with CNS metastases at baseline or a history of CNS metastases [ Time Frame: Approximately 3.0-3.5 years ]

Other Outcome Measures:
Adverse events, including deaths and other serious adverse events [ Time Frame: Approximately 3.0-3.5 years ]
Incidence of clinical laboratory abnormalities (e.g., CBC, serum chemistry and coagulation testing) [ Time Frame: Approximately 3.0-3.5 years ]
Peak plasma concentration (Cmax) of tesetaxel [ Time Frame: Approximately 2.0-2.5 years ]
Area under the plasma concentration versus time curve (AUC) of tesetaxel [ Time Frame: Approximately 2.0-2.5 years ]
The effect of tesetaxel on capecitabine and 5-FU Cmax [ Time Frame: Approximately 2.0-2.5 years ]
The effect of tesetaxel on capecitabine and 5-FU AUC [ Time Frame: Approximately 2.0-2.5 years ]

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 (ER and/or PgR) positive disease based on local testing: ASCO/CAP guidelines
should be utilized for assessing HR status
5. Measurable disease per RECIST 1.1, including bone-only disease with measurable lytic
component.
 Patients with bone-only metastatic cancer must have a measurable 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
measurable 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 Enrollment (defined
as the time of Sponsor approval of treatment dose)
 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 Enrollment
 Prior stereotactic brain radiosurgery is permitted
 CNS surgical resection must have been completed > 28 days prior to the date of
Enrollment; patient must have complete recovery from surgery
6. Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, or 2
(Appendix B)
7. 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.
8. Documented (including de novo): (a) locally advanced breast cancer that is not
considered curable by surgery and/or radiation; or (b) metastatic breast cancer
9. 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
10. Complete recovery to baseline or Grade 1 per National Cancer Institute (NCI) Common
Terminology Criteria for Adverse Events (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
11. Ability to swallow an oral solid-dosage form of medication
12. 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)
13. 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 device or double barrier methods,
including male/female condoms with spermicide and use of contraceptive sponge,
cervical cap, or diaphragm
14. Male patients must use an effective, non-hormonal form of contraception from Screening
throughout the Treatment Phase and until 130 days after the last dose of Study treatment
 Acceptable methods include: male/female condoms with spermicide, or vasectomy
with medical confirmation of surgical success
15. Written informed consent and authorization to use and disclose health information
16. Ability to comprehend and comply with the requirements of the Study

1. Two or more prior chemotherapy regimens for advanced disease
2. Prior treatment with a taxane at any dose
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. 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 Enrollment
11. Major surgery ≤ 28 days prior to the date of Enrollment; patient must have complete
recovery from surgery
12. 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 [refer to Appendix C])
13. History of hypersensitivity or unexpected reactions to capecitabine, or other
fluoropyrimidine agents or any of their ingredients
14. 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.
15. Pregnant or breastfeeding
16. If, in the opinion of the Investigator, the patient is deemed unwilling or unable to comply
with the requirements of the Study
17. Treatment with brivudine, sorivudine, or its chemically-related analogs ≤ 28 days prior to
the date of Enrollment