Sacituzumab Govitecan with or without Chemotherapy before Surgery for the Treatment of Localized Breast Cancer, The NeoSTAR Trial

Inclusion Criteria

• Female or male patients >= 18 years of age
• Histologically confirmed diagnosis of invasive breast cancer, previously untreated
• Pre- and postmenopausal women are eligible to participate if not pregnant, not breastfeeding, and at least one of the following conditions applies: * Not a woman of childbearing potential (WOCBP) OR * A WOCBP who agrees to use contraception during the treatment period and for at least 6 months (corresponding to time needed to eliminate any study treatment(s) (pembrolizumab and/or any active comparator/combination) plus 30 days (a menstruation cycle) for study treatments with risk of genotoxicity] after the last dose of study treatment. * A WOCBP with a negative Urine or serum beta human chorionic gonadotrophin (bHCG) (repeat required if initial test is not within 2 weeks prior to treatment; repeat can be the same day as cycle 1 day 1, and a urine or serum pregnancy test is acceptable; the need for repeat testing should not delay registration)
• Eastern Cooperative Oncology Group (ECOG) performance status = 0, 1 (Karnofsky >= 60%)
• Ability to understand and the willingness to sign a written informed consent form (ICF). Patient has signed the ICF prior to any screening procedures being performed and is able to comply with protocol requirements, including research biopsy
• Absolute neutrophil count (ANC) >= 1,500 per mm^3
• Platelets >= 100,000 per mm^3
• Hemoglobin >= 9.0 g/dL
• Prothrombin time (PT)- International normalized ratio (INR) =< 1.5 x institutional upper limit of normal (ULN) unless participant is receiving anticoagulant therapy as long as PT or activated partial thromboplastin time (aPTT) is within therapeutic range of intended use of anticoagulants (for patients receiving pembrolizumab only).
• Serum creatinine < 1.5 mg/dL or creatinine clearance >= 50 mL/min (via the Cockcroft-Gault formula) for participants with creatinine levels above institutional ULN
• Total bilirubin =< 1.5 x ULN
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 2.5 x ULN
• Serum albumin > 3 g/dL
• TRIPLE NEGATIVE BREAST CANCER COHORTS: Participants must have biopsy proven ER negative (ER-), PR negative (PR-),HER2 negative (HER2-), invasive breast cancer. ER, PR, and HER2 positivity would be determined per American Society of Clinical Oncology (ASCO)/ College of American Pathologist (CAP) guidelines by institutional (local) assessment. Participants with low ER and PR (≤ 10%) are eligible for the TNBC cohort. The decision will be based on physician discretion.
• TRIPLE NEGATIVE BREAST CANCER COHORTS: Patients with multi-focal and multicentric disease are eligible provided all histologically examined lesions are ER-/PR-/HER2- (local assessment). The need to biopsy additional lesions is at the discretion of the treating physician. Patients with bilateral invasive breast cancer are eligible provided all histologically examined lesions are ER-/PR-/HER2- (local assessment).
• TRIPLE NEGATIVE BREAST CANCER COHORTS: For Cohort A1, the primary tumor (at least one lesion) must be 1 cm or greater measured by radiological imaging, and for Cohort A2 2 cm or greater measured by radiological imaging or by physical exam. Patient with regional lymph node American Joint Committee on Cancer (AJCC) (version [v] 8) TNM stages N0-N2. If node positive, any primary tumor size is permissible for either cohort A1 or A2. Absence of distant metastatic disease (AJCC TNM stage M0). Staging scans are not required and are per discretion of the treating physician.
• HORMONE RECEPTOR POSITIVE/HER2 NEGATIVE COHORTS: Participants must have a histologically or cytologically confirmed diagnosis of HR+/HER2- (ER and/or PR >= 1% by immunohistochemistry) and HER2-negative invasive breast cancer per current ASCO/CAP guidelines.
• HORMONE RECEPTOR POSITIVE/HER2 NEGATIVE COHORTS: Patients with multifocal, multicentric or bilateral disease are eligible, if not known to be HER2-positive.
• HORMONE RECEPTOR POSITIVE/HER2 NEGATIVE COHORTS: Participants must have operable breast cancer and be considered candidates for neoadjuvant chemotherapy.
• HORMONE RECEPTOR POSITIVE/HER2 NEGATIVE COHORTS: Anatomic clinical stage II-III (per AJCC 8th edition). Primary tumor (at least one lesion) must be > 1.0 cm measured by radiological imaging or physical exam. Breast imaging should include imaging of the ipsilateral axilla. Participants must not have any evidence of distant metastatic disease (AJCC TNM stage M0). Staging scans are not required and are per discretion of the treating physician
• HORMONE RECEPTOR POSITIVE/HER2 NEGATIVE COHORTS: Genomic high-risk as defined by at least one of the following: * Oncotype recurrence score (RS) >25 * Prosigna risk of recurrence (ROR) score > 40 * MammaPrint high-risk High-risk per genomic assay is not required in the following instances: ** For premenopausal: *** Any cN1 and histologic grade 2/3 *** Any cN2/N3 *** Any cT4 ** For postmenopausal: *** Any cN2/N3 *** Any cT4
• INFLAMMATORY BREAST CANCER COHORT: Clinical diagnosis of inflammatory breast cancer (IBC) involving an intact breast. The diagnosis of IBC will follow the recently published defined criteria for IBC to ensure that the definition of IBC is not subjective. The classification of IBC diagnosis will be made using the Scoring System for IBC, if the total score is 25-41 (strong possibility of IBC) or > 41 (definitely IBC). Only patients with scores of 25 or higher will be enrolled in this trial in the IBC cohort. Patients with scores lower than 25 may be eligible for the other cohorts
• INFLAMMATORY BREAST CANCER COHORT: Newly diagnosed, locally advanced, HER2-negative (as per ASCO/CAP guidelines) invasive breast cancer. Any ER and PR is allowed.
• INFLAMMATORY BREAST CANCER COHORT: Patients with evidence of extensive nodal involvement are allowed. Extensive nodal involvement is defined as metastatic disease involving any regional nodal region outside of the involved breast.
• INFLAMMATORY BREAST CANCER COHORT: Patients may have bilateral breast cancer so long as one breast meets criteria for IBC, and neither breast cancer has received prior therapy
• INFLAMMATORY BREAST CANCER COHORT: No prior breast cancer diagnosis in the breast affected with IBC
• COHORTS WITH PEMBROLIZUMAB: History of hypersensitivity reactions attributed to compounds of similar chemical or biologic composition to pembrolizumab. Has severe hypersensitivity (>= Grade 3) to pembrolizumab and/or any of its excipients.

Exclusion Criteria

• Participants currently receiving systemic therapy for any other malignancy or having received systemic therapy for a malignancy in the preceding 3 years (Concurrent endocrine therapy allowed in the adjuvant setting. Concurrent GnRH agonists allowed in any setting. Concurrent CDK4/6 inhibitor not allowed in any setting.)
• Uncontrolled inter-current illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
• Clinically significant, uncontrolled heart disease and/or cardiac repolarization abnormality including any of the following: * History of angina pectoris, symptomatic pericarditis, coronary artery bypass graft (CABG) or myocardial infarction within 6 months prior to study entry * History of cardiac failure, known cardiomyopathy (left ventricular ejection fraction [LVEF] < 50%; new LVEF assessment is not specifically required for this trial), significant/symptomatic bradycardia, long QT syndrome, family history of idiopathic sudden death or congenital long QT syndrome or any of the following: ** Known risk to prolong the QT interval or induce Torsade’s de Pointes ** Uncorrected hypomagnesemia or hypokalemia ** Systolic blood pressure (SBP) > 160 mmHg or < 90 mmHg. Higher blood pressure is permissible per discretion of treating physician. ** Bradycardia (heart rate < 50 at rest), by electrocardiogram (ECG) or pulse * On screening, inability to determine the Fridericia's correction formula (QTcF) interval on the ECG (i.e.: unreadable or not interpretable) or QTcF > 470 screening ECG
• Pregnant or breast-feeding women are excluded from this study because the safety of study medications is not established
• HIV-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months prior to enrollment are eligible for this trial. Participants who are hepatitis B antigen (HBsAg) positive are eligible if they have received hepatitis B virus (HBV) antiviral therapy for at least 4 weeks and have undetectable HBV viral load prior to registration. Participants should remain on anti-viral therapy throughout study intervention and follow local guidelines for HBV anti-viral therapy post completion of study intervention. Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load
• Participants who are not good candidates for the study (as per investigator judgement)
• Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception throughout the study and for 8 weeks after study drug discontinuation. Women are considered post-menopausal and not of child bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g., age appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks ago. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered not of child bearing potential. Barrier method plus spermicide alone is not considered highly effective contraception but could be combined with other highly effective contraception methods. Highly effective contraception methods permissible on study include: * Total abstinence when this is in line with the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post ovulation methods) and withdrawal are not acceptable methods of contraception * Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy), total hysterectomy, or tubal ligation at least six weeks before taking study treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment * Non-hormonal intrauterine device (IUD) * While generally not recommended, if deemed clinically appropriate by the treating physician: Use of oral, injected or implanted hormonal methods of contraception or placement of an intrauterine device (IUD) or intrauterine system (IUS), or other forms of hormonal contraception that have comparable efficacy (failure rate < 1%), for example hormone vaginal ring or transdermal hormone contraception.
• Males with female partners of childbearing potential unless they use the following contraceptive methods: * Total abstinence when this is in line with the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post ovulation methods) and withdrawal are not acceptable methods of contraception * Use a male condom plus partner use of a contraceptive method with a failure rate of <1% per year * Vasectomy (upon medical assessment of surgical success)
• History of hypersensitivity reactions attributed to compounds of similar chemical or biologic composition to sacituzumab govitecan
• COHORTS WITH PEMBROLIZUMAB: History of active, noninfectious pneumonitis that required treatment with steroids
• COHORTS WITH PEMBROLIZUMAB: History of interstitial lung disease
• COHORTS WITH PEMBROLIZUMAB: Participants who are currently receiving chronic treatment with corticosteroids at a dose >= 10 mg of prednisone (or its glucocorticoid equivalent) per day (inhaled and topical steroids are allowed), or any other chronic immunosuppressive treatment that cannot be discontinued prior to starting study drug
• COHORTS WITH PEMBROLIZUMAB: Participant has received a live vaccine within 30 days prior to registration. Use of the inactivated seasonal influenza vaccine is allowed
• COHORTS WITH PEMBROLIZUMAB: Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study intervention * Participants who have entered the follow-up phase of an investigational study may participate as long as it has been 4 weeks after the last dose of previous investigational agent.
• COHORTS WITH PEMBROLIZUMAB: Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment and is allowed.
• COHORTS WITH PEMBROLIZUMAB: Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug
• COHORTS WITH PEMBROLIZUMAB: Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the participant’s participation for the full duration of the study, or is not in the best interest of the participant to participate, in the opinion of the treating investigator.
• COHORTS WITH PEMBROLIZUMAB: Has a known history of Human Immunodeficiency Virus (HIV) infection, unless on effective anti-retroviral therapy with undetectable viral load within 6 months prior to enrollment.
• COHORTS WITH PEMBROLIZUMAB: Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
• COHORTS WITH PEMBROLIZUMAB: Has had an allogenic tissue/solid organ transplant