Neoadjuvant Nivolumab and Chemotherapy in Patients With Localized Triple-negative Breast Cancer

Inclusion Criteria:

• Histologically or cytologically confirmed newly diagnosed ER-/HER2- breast cancer.ER and PR < Allred score of 3 or < 1% positive staining cells in the invasivecomponent of the tumor. HER2 negative by FISH or IHC staining 0 or 1+ according toNCCN guidelines.

• Clinical stage II or III (by AJCC 8th edition at least T2, any N, M0 or if N+ thenany T) breast cancer eligible for neoadjuvant chemotherapy with complete surgicalexcision of the breast cancer after neoadjuvant therapy as the treatment goal.

• Tumor size at least 2 cm in one dimension by clinical or radiographic exam (WHOcriteria). Patients with histologically confirmed or clinically palpable lymph nodesmay be enrolled regardless of tumor size. A palpable mass is not required as long asthe mass is at least 2 cm in one dimension by radiographic exam. 2D measurementsshould be completed during screening if available.

• No prior therapy for this disease

• At least 18 years of age.

• Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1

• Normal bone marrow and organ function as defined below:

• Leukocytes ≥ 2,000/mcL (stable off any growth factor within 4 weeks of firststudy treatment administration)

• Absolute neutrophil count ≥ 1,500/mcL (stable off any growth factor within 4weeks of first study treatment administration)

• Platelets ≥ 100,000/mcL (stable off any growth factor within 4 weeks of firststudy treatment administration)

• Hemoglobin ≥8.5 g/dl (transfusion to achieve this level is not permitted within 2 weeks of first study treatment administration)

• Total bilirubin ≤ 1.5 x institutional upper limit of normal (IULN) (exceptparticipants with Gilbert's Syndrome who must have normal direct bilirubin)

• AST(SGOT)/ALT(SGPT) ≤ 2.0 x IULN

• Alkaline phosphatase <2.5 x ULN

• Serum creatinine < 1.5 x ULN or creatinine clearance > 40 mL/min byCockcroft-Gault

• Albumin ≥ 3 g/dL

• INR and aPTT <1.5 x IULN (This applies only to patients who do not receivetherapeutic anticoagulation; patients receiving therapeutic anticoagulation,such as low-molecular-weight heparin or warfarin, should be on a stable dose).

• Women of childbearing potential (WOCBP) must have a negative serum or urinepregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24hours prior to the start of study treatment.

• Women must not be breastfeeding.

• WOCBP must agree to follow instructions for method(s) of contraception for theduration of treatment with study treatment(s) and for a total of 5 monthspost-treatment completion.

• Ability to understand and willingness to sign an IRB approved written informedconsent document (or that of legally authorized representative, if applicable).

• Consent for fresh pre-treatment, on-treatment, biopsy samples at acceptable clinicalrisk, as judged by the investigator.

• Participants must be willing and able to comply with scheduled visits, treatmentschedule, and laboratory testing

Exclusion Criteria:

• Prior treatment with immunotherapy for cancer

• Known metastatic disease

• Known invasive cancer in contralateral breast

• Patients with a previous history of non-breast malignancy are eligible only if theymeet the following criteria for a cancer survivor:

• Has undergone potentially curative therapy for all prior malignancies AND

• Has been considered disease-free for at least 1 year (with the exception ofbasal cell or squamous cell carcinoma of the skin or carcinoma-in-situ of thecervix.

• Currently receiving any other investigational agents.

• A history of allergic reactions attributed to compounds of similar chemical orbiologic composition to paclitaxel, carboplatin, nivolumab, or other agents used inthe study. Patients who have received multiple blood transfusions.

• Evidence of uncontrolled ongoing or active infection, requiring parenteralanti-bacterial, anti-viral, or anti-fungal therapy ≤ 7 days prior to administrationof study treatment. Patients receiving prophylactic antibiotics (e.g., forprevention of a urinary tract infection or chronic obstructive pulmonary disease)are eligible.

• Patients with prior allogeneic bone marrow transplantation or prior solid organtransplantation.

• History or risk of autoimmune disease, including, but not limited to, systemic lupuserythematosus, rheumatoid arthritis, inflammatory bowel disease (Crohn's disease andulcerative colitis), vascular thrombosis associated with antiphospholipid syndrome,Wegener's granulomatosis, Sjögren's syndrome, Bell's palsy, Guillain-Barré syndrome,multiple sclerosis, autoimmune thyroid disease, vasculitis, or glomerulonephritis.

• Patients with a history of autoimmune hypothyroidism on a stable dose ofthyroid replacement hormone may be eligible.

• Patients with controlled Type 1 diabetes mellitus on a stable insulin regimenmay be eligible.

• Patients with eczema, psoriasis, lichen simplex chronicus of vitiligo withdermatologic manifestations only (e.g., patients with psoriatic arthritis wouldbe excluded) are permitted provided that they meet the following conditions:

• Patients with psoriasis must have a baseline ophthalmologic exam to ruleout ocular manifestations

• Rash must cover less than 10% of body surface area (BSA)

• Disease is well controlled at baseline and only requiring low potencytopical steroids (e.g., hydrocortisone 2.5%, hydrocortisone butyrate 0.1%,flucinolone 0.01%, desonide 0.05%, aclometasone dipropionate 0.05%)

• No acute exacerbations of underlying condition within the last 12 months (not requiring psoralen plus ultraviolet A radiation [PUVA], methotrexate,retinoids, biologic agents, oral calcineurin inhibitors; high potency ororal steroids)

• History of idiopathic pulmonary fibrosis, pneumonitis (including drug induced),organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizingpneumonia, etc.), or evidence of active pneumonitis on screening chest computedtomography (CT) scan.

• Uncontrolled or significant cardiovascular disease

• History of any chronic hepatitis as evidenced by the following:

• Positive test for hepatitis B surface antigen

• Positive test for qualitative hepatitis C viral load (by polymerase chainreaction [PCR]).

• Positive test for latent tuberculosis (TB) at screening (e.g. T-SPOT or Quantiferontest) or evidence of active TB.

• Major surgical procedure within 28 days prior to Cycle 1, Day 1 or anticipation ofneed for a major surgical procedure during the course of the study with theexception of the planned breast cancer surgery that is part of the trial design.Participants must have recovered from the effects of major surgery or significanttraumatic injury at least 14 days before the first dose of study treatment.

• Any uncontrolled medical condition which, in the opinion of the Investigator, wouldpose a risk to participant safety or interfere with study participation orinterpretation of individual participant results.

• Treatment with systemic immunosuppressive medications (including, but not limitedto, prednisone, cyclophosphamide, azathioprine, methotrexate, thalidomide, andanti-tumor necrosis factor [anti-TNF] agents) within 2 weeks prior to Cycle 1, Day

• Patients who have received acute, low dose, systemic immunosuppressantmedications (e.g., a one-time dose of dexamethasone for nausea) may beenrolled.

• The use of inhaled corticosteroids and mineralocorticoids (e.g.,fludrocortisone) for patients with orthostatic hypotension or adrenocorticalinsufficiency is allowed. The use of replacement doses of prednisone or othercorticosteroid for adrenocortical insufficiency is allowed

• Participants with a condition requiring systemic treatment with eithercorticosteroids (> 10 mg daily prednisone equivalents) or otherimmunosuppressive medications within 14 days of start of study treatment.Inhaled or topical steroids and adrenal replacement steroid doses > 10 mg dailyprednisone equivalent are permitted in the absence of active autoimmunedisease.

• Evidence of coagulopathy or bleeding diathesis.

• Ascites needing paracentesis or medical management.

• Patients positive for human immunodeficiency virus (HIV) are NOT excluded from thisstudy, but HIV-positive patients must have:

• A stable regimen of highly active anti-retroviral therapy (HAART)

• No requirement for concurrent antibiotics or antifungal agents for theprevention of opportunistic infections

• A CD4 count above 250 cells/mcL and an undetectable HIV viral load on standardPCR-based tests