HR+/HER2- Advanced or Metastatic Breast Cancer Patients Treated With Sacituzumab Govitecan

Inclusion Criteria:

1. Provision of signed and dated, written informed consent form prior to any mandatorystudy specific procedures, sampling, and analyses.

2. Patients must be male or female (pre/peri or postmenopausal) ≥ 18 years of age.

3. ECOG performance status of 0 or 1(see Appendix 1).

4. Histologically or cytologically confirmed breast cancer with evidence of locallyadvanced disease, not amenable to resection or radiation therapy with curativeintent or metastatic disease.

5. HR+/HER2- BC by local testing, not amenable to surgical therapy will be enrolled inthis study.

6. HER2 negativity is defined as either of the following by local laboratoryassessment: IHC 0, IHC 1+ or IHC2+/in situ hybridization (ISH) negative as perthe most recent American Society of Clinical Oncology (ASCO)-College ofAmerican Pathologists Guideline (CAP) guideline. If a patient has had multipleHER2 results after metastatic disease, the most recent test result priorscreening period will be used to confirm eligibility.

7. ER and/or PR positivity are defined as >1% of cells expressing HR via IHCanalysis as per most recent ASCO-CAP guideline. If a patient has had multipleER/PgR results after metastatic disease, the most recent test result priorscreening period will be used to confirm eligibility.

8. Disease refractory to CDK4/6 inhibitors, defined as recurrence during or within 12months after the end of adjuvant treatment or progression during or within 6 monthsafter the end of treatment for advanced/metastatic disease.

9. No more than 1 prior systemic chemotherapy or antibody-drug conjugate (ADC) regimensfor metastatic disease. Adjuvant or neoadjuvant therapy for early-stage disease willqualify as one of the required prior chemotherapy regimens if the development ofunresectable, locally advanced, or metastatic disease occurred within a 12-monthperiod of time of the therapy. Note: treatments for bone metastases (eg,bisphosphonates, denosumab, etc.), targeted therapies (eg, PARP inhibitors, CDK 4/6inhibitors, immunotherapy etc.) and hormonal therapy are not considered as priorsystemic chemotherapy treatments for advanced disease.

10. Radiologic or objective evidence of disease progression on or after the lastsystemic therapy prior to starting study treatment

11. Measurable or non-measurable disease but evaluable (identification of target and/ornon-target lesions by RECIST Vs1.1).

12. Patients must have a site of disease amenable to safely perform a biopsy, as perInvestigator's assessment, and be a candidate for tumor biopsy according to thetreating institution's guidelines.

13. Possibility of performing a biopsy prior to the start of treatment and itsrepetition after 2 weeks (14-21 days) and at End of Treatment (EOT) on the samelocation. It will be provided formalin-fixed paraffin-embedded (FFPE) tumor block.The tumor tissue should be of good quality based on total and viable tumor contentand must be evaluated centrally for quality prior to enrollment. Patients whosetumor tissue is not evaluable for central testing are not eligible. It isrecommended to send the biopsy directly to the central lab after confirming theexistence of a tumor, so as not to delay the inclusion, without the need to carryout IHC studies in the same sample.

• Acceptable samples include core needle biopsies for deep tumor tissue orexcisional, incisional, punch, or forceps biopsies for cutaneous, subcutaneous,bone or mucosal lesions or biopsies from bone metastases. Lymph node biopsiesare also permitted.

• Fine needle aspiration, brushing, cell pellet from pleural effusion and lavagesamples are not acceptable.

12. Patients must have normal organ and bone marrow function measured within 35 daysprior to administration of study treatment as defined below:

• Haemoglobin ≥ 9.0 g/dL *

• Absolute neutrophil count (ANC) ≥ 1.5 x 109/L*

• Platelet count ≥ 100 x 109/L*

• Total bilirubin (TBL) ≤ 1.5 × upper limit of normal (ULN) or ≤ 3 × ULN in thepresence of documented Gilbert's Syndrome (unconjugated hyperbilirubinemia).

• AST (SGOT) / ALT (SGPT) ≤ 2.5 x ULN unless liver metastases are present inwhich case, they must be ≤ 5x ULN

• Creatinine ≤ 1.5 x ULN or Creatinine clearance estimated of ≥30mL/min using theCockcroft-Gault equation.

• Serum albumin >3 g/dL

• International normalized ratio (INR) or prothrombin time (PT) and eitherpartial thromboplastin or activated partial thromboplastin time (aPTT) ≤ 1.5 ×ULN *Without transfusional or growth factor support within 1 week of studytreatment initiation.

13. Patients must have a life expectancy ≥ 16 weeks.

14. Male patients and female patients of childbearing potential who engage inheterosexual intercourse must agree to use protocol-specified method(s) ofcontraception as described in Appendix 2.

15. Willing and able to comply with the requirements and restrictions in this protocol.

Exclusion Criteria:

1. Patients with HER2-positive or TNBC disease.

2. Other malignancy unless curatively treated with no evidence of disease for ≥3 yearsexcept: non-melanoma skin cancer, in situ cancer of the cervix, ductal carcinoma insitu (DCIS), Stage 1, grade 1 endometrial carcinoma or other malignant tumors withan expected curative outcome after medical monitor approval.

3. Has unresolved toxicities from previous anticancer therapy (≥ CTCAE version 5.0grade 1) caused by previous cancer therapy, excluding alopecia or other toxicitiesnot considered a safety risk for the patient at investigator's discretion. Note:Subjects may be enrolled with chronic, stable Grade 2 toxicities (defined as noworsening to ≥Grade 2 for at least 2 months prior to enrollment and managed withstandard of care treatment) that the investigator deems related to previousanticancer therapy, such as: Chemotherapy-induced neuropathy, Fatigue, Residualtoxicities from prior IO treatment Grade 1 or Grade 2 endocrinopathies. Note: ifpatients received major surgery, they must have recovered adequately from thetoxicity and/or complications from the intervention prior to starting therapy.

4. Patients may not be participating in a study with an investigational agent orinvestigational device within 2 weeks or 5 half-lives, whichever is longer, prior toallocation. Patients participating in observational studies are eligible.

5. Patients with symptomatic uncontrolled brain metastases. Participants with a historyof treated Central Nervous System (CNS) metastases are eligible, provided they meetall of the following criteria:

• Biopsiable disease outside the CNS is present.

• No evidence of interim CNS progression between the completion of CNS directedtherapy and the screening radiographic study.

• Metastases are limited solely to cerebellar and supratentorial lesions.

• Stable requirement for corticosteroids (≤ 20 mg oral prednisone or equivalent)or anticonvulsants during >4 weeks as therapy for CNS disease.

• No stereotactic radiation within 7 days or whole-brain radiation within 14 daysprior to enrolment.

• No evidence of progression or haemorrhage after completion of CNS directedtherapy.

• Patients with spinal cord compression are excluded unless considered to havereceived definitive treatment for this and evidence of clinically stabledisease for 28 days.

6. History of significant cardiovascular disease, defined as:

• New York Heart Association Class III or greater congestive heart failure orknown left ventricular ejection fraction of < 40%.

• Unstable angina or myocardial infarction within 6 months before enrolment.

• History of serious ventricular arrhythmia (ie, ventricular tachycardia orventricular fibrillation), high-grade atrioventricular block, or other cardiacarrhythmias requiring antiarrhythmic medications (except for atrialfibrillation that is well controlled with antiarrhythmic medication); historyof QT interval prolongation.

7. Have active chronic inflammatory bowel disease (ulcerative colitis, Crohn's disease)or GI perforation within 6 months of enrollment.

8. Have active serious infection requiring requiring IV antibiotics, antivirals, orantifungals.

9. Have a known history of Human Immunodeficiency Virus (HIV).

10. Have active HBV (defined as having a positive HbsAg test) or HCV.

11. For patients with a history of HBV infection, a hepatitis B core antibody testshould be conducted at screening. If positive, hepatitis B DNA testing will beperformed and if active HBV infection is ruled out, the patient may beeligible.

12. Patients who are HCV antibody positive with polymerase chain reaction negativefor HCV RNA may be eligible.

13. Have other concurrent medical or psychiatric conditions that, in the investigator'sopinion, may be likely to confound study interpretation or prevent completion ofstudy procedures and follow-up examinations.

14. Has received a live vaccine within 30 days prior to randomization.

15. Prior treatment with Sacituzumab-govitecan.

16. Known or severe (≥ Grade 3) hypersensitivity or allergy to sacituzumab govitecan,their metabolites, or formulation excipient.

17. Requirement for ongoing therapy with or prior use of any prohibited medicationslisted in Section 7.5.

18. Positive serum pregnancy test or women who are lactating (see Appendix 2).