Peri-Operative Immune Checkpoint Inhibition and Cryoablation in Women with Triple-negative Breast Cancer

Inclusion Criteria:

1. Women age 18 years or older

2. Confirmed histologic diagnosis of invasive carcinoma of the breast

3. Pathology confirmation of invasive carcinoma (reported or requested and pending)

4. ER, PR and HER2 negative on outside or Cedars Sinai biopsy report, where ER and PRnegative are defined as staining present in ≤10% of invasive cancer cells by IHC,and HER2-negative is defined as IHC 0-1+ or FISH <2.0. If ER, PR and HER2 status arenot reported the results must be requested and pending.

5. Operable tumor measuring ≥1.0 cm in maximal diameter

6. Any nodal status allowed, including negative nodal status.

7. Multifocal and multicentric disease is permitted if all foci have been biopsied andalso meet the criteria for TNBC.

8. Synchronous bilateral invasive breast cancer is permitted if all foci have beenbiopsied and also meet the criteria for TNBC.

9. No indication of distant metastases

10. Total mastectomy or lumpectomy planned

11. Tumor amenable to cryoablation as determined by a study radiologist

12. ECOG performance status score of 0 or 1.

13. Screening laboratory values must meet the following criteria:

• White blood cells (WBCs) ≥ 2000/μL

• Absolute neutrophil count (ANC) ≥ 1500/μL

• Platelets ≥ 100 x 103/μL ii. Hemoglobin ≥ 9.0 g/dL iii. Serum creatinine ≤ 1.5x ULN or creatinine clearance (CrCl) ≥ 40 mL/min (if using the Cockcroft-Gaultformula below): Female CrCl = (140 - age in years) x weight in kg x 0.85 72 xserum creatinine in mg/dL

• AST/ALT ≤ 3 x upper limit of normal (ULN)

• Bilirubin ≤ 1.5 x ULN (except subjects with Gilbert's syndrome, who must havetotal bilirubin < 3.0 mg/dL)

14. Women of childbearing potential (WOCBP) must use appropriate method(s) ofcontraception. WOCBP should use an adequate method to avoid pregnancy for 23 weeks (30 days plus the time required for nivolumab and, ipilimumab, and pembrolizumab toundergo five half-lives) after the last dose of investigational drug.

15. Women of childbearing potential must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG). Women must not bebreastfeeding

16. Willing to adhere to the study visit schedule and the prohibitions and restrictionsspecified in this protocol.

Exclusion Criteria:

• Medical history and concurrent diseases

1. Has an active autoimmune disease that has required systemic treatment in thepast 2 years (i.e., with use of disease modifying agents, corticosteroids, orimmunosuppressive drugs). Note: Replacement therapy (eg, thyroxine, insulin, orphysiologic corticosteroid replacement therapy for adrenal or pituitaryinsufficiency) is not considered a form of systemic treatment.

2. Any underlying medical or psychiatric condition, which in the opinion of theinvestigator, will make the administration of study drug hazardous or obscurethe interpretation of AEs, such as a condition associated with frequent orpoorly controlled diarrhea.

3. A history of invasive malignancy ≤5 years prior to signing informed consentexcept for adequately treated basal cell or squamous cell skin cancer, or insitu cervical cancer, or ovarian cancer.

4. Has known active hepatitis B or hepatitis C.

• Prohibited Treatments and/or Therapies

1. Chronic use of immunosuppressants and/or systemic corticosteroids (used in themanagement of cancer or non-cancer-related illnesses). Brief periods of steroiduse, for example for the management of chemotherapy-associated toxicities, areallowed. The use of corticosteroids on study is allowed for the treatment ofimmune related adverse events (irAEs) and other medical conditions includingadrenal insufficiency.

2. Any non-oncology live vaccine therapy used for prevention of infectiousdiseases within 3 weeks prior to first dose of ICI.

3. Prior investigational agents within 3 weeks prior to ICI administration