Cemiplimab in High Risk or Locally Advanced Hormone Receptor Positive HER2 Negative or Triple-Negative Breast Cancer
Cemiplimab in High Risk or Locally Advanced Hormone Receptor Positive HER2 Negative or Triple-Negative Breast Cancer
This is a single-arm, open-label, phase 2 study that will enroll 36 subjects, who have
 pathologically proven diagnosis of invasive breast cancer, clinical stage tumor 1-3 (cT1-T3),
 node 0-3 (cN0-N3), metastasis 0 (cM0), hormone receptor positive (HR+)
 (estrogen-receptor-positive (ER+) and/or progesterone-receptor-positive (PR+) human epidermal
 growth factor receptor 2 (HER2) negative or hormone receptor-negative (HR-)
 (estrogen-receptor-negative (ER-) and progesterone-receptor-negative (PR-) human epidermal
 growth factor receptor 2 (HER2) negative/triple-negative breast cancer.
Hypothesis: The addition of cemiplimab (PD-1 inhibitor) to standard neoadjuvant chemotherapy
 in patients with locally advanced HR+ HER2 negative or triple-negative (TN) breast cancer
 having positive PD-L1 and/or PD-L2 tumor expression will be associated with an increase in
 pathologic complete response of at least 20%.

 Primary Objectives:

 Assess pathologic responses in patients treated with neoadjuvant chemotherapy and cemiplimab.
Inclusion Criteria:

 1. Pathologically proven diagnosis of invasive breast cancer, cT1-T3, cN0-N3, cM0, HR+
 (ER+ and/or PR+) HER2 negative or HR- (ER- and PR-) HER2 negative/triple negative
 breast cancer.

 2. Tumors with positive PD-L1 and/or PD-L1 protein expression. Positivity is defined as
 PD-L1 and/or PD-L2 expression of ≥ 1% of immune cells within the stroma or in cancer
 cells.

 3. Estrogen and/or progesterone receptor positive tumor defined ≥1% positively staining
 cells by immunohistochemistry, according to the current American Society of Clinical
 Oncology (ASCO) / College of American Pathologists (CAP) guidelines.

 4. HER2/neu must be negative by immunohistochemistry (IHC) defined as IHC 0 or 1+ or
 fluorescence in situ hybridization (FISH) or other ISH methods with a ratio of < 2
 according to current ASCO (American Society of Clinical Oncology)/CAP guidelines.

 5. Candidate for neoadjuvant chemotherapy due to their clinical stage or subtype of
 breast cancer as decided by the treating physician.

 6. Breast imaging with mammogram and/or ultrasound and/or MRI is per standard of care for
 diagnosis, but at least one modality of imaging must be completed within 30 days of
 registration.

 7. Systemic imaging with CT scan, bone scan, positron emission tomography (PET) scan or
 MRI if clinically indicated per treating physician's discretion.

 8. Left ventricular ejection fraction (LVEF) ≥ lower limit of normal (per institutional
 normal) determined by echocardiogram or nuclear medicine scan within 30 days of
 registration.

 9. The patient must be female.

 10. Age ≥18 years.

 11. Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2.

 12. The patient must provide study-specific informed consent prior to study entry.

 13. Patients with a prior history of contralateral breast cancer will be considered
 eligible, if they have completed all treatment (including endocrine therapy) more than
 two years prior to registration.

 14. Patients must not have had a prior treatment for this breast cancer or for any
 malignancy diagnosed or treated within the past two years, with the exception of
 non-melanomatous skin cancer, carcinoma in situ of the cervix and contralateral breast
 cancer, as described above.

 15. Patients with bilateral breast cancer are also eligible provided HER2 negativity is
 documented on both right and left breast cancer and patient is deemed to be a
 candidate for neoadjuvant chemotherapy by treating physician.

 16. Patients with multicentric or multifocal disease are eligible if they are a candidate
 for neoadjuvant chemotherapy.

 17. Patients must meet one of the following:

 -  Postmenopausal for at least one year before the screening visit, or

 -  Surgically sterile, or

 -  If they are of childbearing potential, negative pregnancy test within 14 calendar
 days prior to registration for women of childbearing potential

 -  Women of childbearing age must use at least two adequate methods of contraception
 during the treatment period and at least 6 months from the last dose of
 chemotherapy. Examples of contraceptives include barrier methods, intrauterine
 devices (IUDs) hormonal or copper, oral contraceptive pills, and abstinence.
 Hormonal methods are not to be used by patients with HR+ breast cancer.

 18. Adequate organ function with baseline lab values.

 -  Absolute neutrophil count (ANC) ≥ 1500/µL

 -  Hemoglobin (Hb) ≥ 8g/dL

 -  Platelet count ≥ 100,000/µL

 -  Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3x
 institutional upper limit of normal (ULN)

 -  Serum bilirubin within ≤ 1.5 x ULN except patients with Gilbert's syndrome for
 whom the direct bilirubin should be within normal range.

 -  Creatinine clearance of ≥ 30 mL/min

 -  International normalized ratio (INR) and activated partial thromboplastin time
 (aPTT) ≤ 1.5 x ULN. This applies to patients not receiving therapeutic
 anticoagulation. Patients on therapeutic anticoagulation should be on a stable
 dose.

 -  Thyroid-stimulating hormone (TSH) ≤ institutional ULN

 Exclusion Criteria:

 1. Patients with clinical or pathologically proven metastatic disease.

 2. HER2 positive disease as determined by either ISH or 3+ on IHC.

 3. Synchronous non-breast malignancy (exceptions include non-melanomatous skin cancer,
 carcinoma in situ of the cervix).

 4. Purely noninvasive breast cancer (i.e., ductal carcinoma in situ, lobular carcinoma in
 situ) without any concurrent invasive breast cancer

 5. Men with breast cancer. Male breast cancer is a rare event.

 6. Medical, psychiatric or other conditions that would prevent the patient from receiving
 the protocol therapy or providing informed consent.

 7. Pregnant or lactating women are ineligible.

 8. Treatment with any investigational drug within 30 days of registration. Prior
 treatment with any immunotherapy or chemotherapy for this breast cancer.

 9. Current grade ≥ 2 peripheral neuropathy (according to NCI CTCAE v. 5.0).

 10. Cardiopulmonary dysfunction defined as: Inadequately controlled angina, heart failure
 or serious cardiac arrhythmia not controlled by adequate medication.

 11. Active Hepatitis B defined as positive Hep B surface antigen (HBsAg) or Hepatitis C.
 Patients with previous hepatitis B virus (HBV) infection or resolved HBV infection
 (defined as having a negative HBsAg test and a positive antibody to hepatitis B core
 antigen [anti-HBc] antibody test) are eligible. If HBV DNA testing is positive, the
 patient is not eligible for study participation. Patients positive for hepatitis C
 virus (HCV) antibody are eligible only if polymerase chain reaction (PCR) is negative
 for HCV RNA.

 12. Positive test for HIV.

 13. History of symptomatic CHF⎯Grade ≥ 3 per NCI CTCAE v5.0 or New York Heart Association
 (NYHA) Class ≥ II.

 14. History of autoimmune disease, including but not limited to myasthenia gravis,
 autoimmune myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid
 arthritis, inflammatory bowel disease, vascular thrombosis associated with
 antiphospholipid syndrome, Wegener granulomatosis, Sjögren's syndrome, Guillain-Barré
 syndrome, multiple sclerosis, vasculitis, or glomerulonephritis.

 -  Patients with a history of autoimmune-related hypothyroidism on a stable dose of
 thyroid replacement hormone may be eligible for this study.

 -  Patients with controlled Type 1 diabetes mellitus on a stable insulin regimen are
 eligible for this study.

 -  Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with
 dermatologic manifestations only (e.g., patients with psoriatic arthritis) are
 eligible, provided the disease has no systemic manifestations and requires only
 low potency topical steroids (e.g., hydrocortisone 2.5%, hydrocortisone butyrate
 0.1%, fluocinolone 0.01%, desonide 0.05%, alclometasone dipropionate 0.05%).

 15. Treatment with systemic corticosteroids or other systemic immunosuppressive
 medications (including but not limited to prednisone, dexamethasone, cyclophosphamide,
 azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor (TNF) agents)
 within 2 weeks prior to study entry, or anticipated requirement for systemic
 immunosuppressive medications during the study. Patients who have received acute,
 low-dose, systemic immunosuppressant medications equivalent to ≤ 10mg of prednisone
 within the 7 days prior to study entry (small dose of dexamethasone for nausea, short
 course for upper respiratory tract infection etc.) may be enrolled in the study.