Peri-Operative Ipilimumab+Nivolumab and Cryoablation Versus Standard Care in Women With Triple-negative Breast Cancer

The purpose of this study is to determine the impact of pre-operative cryoablation,
ipilimumab and nivolumab versus standard pre-operative care on on 3-year Event Free Survival
(EFS), in women with triple negative breast cancer after taxane-based neoadjuvant
chemotherapy. Our strategy combines two interventions: induced activation and maturation of
dendritic cells and tumor-specific T cells by cross-presentation of tumor antigens via local
destruction of tumor tissue by cryoablation. Second, we administer ipilimumab, a CTLA4
blocking antibody that enhances the magnitude and potency of the tumor specific T cell
response, with nivolumab, a PD-1 blocking antibody that interferes with PD-1 mediated T-cell
regulatory signaling. Women with residual triple negative resectable breast cancer after
neoadjuvant chemotherapy will be randomized to standard peri-operative management versus
tumor cryoablation with pre-operative nivolumab and ipilimumab followed post-operative
nivolumab. Women undergoing either mastectomy or breast conserving surgery are eligible.

Inclusion Criteria:

- Women age 18 years or older

- Confirmed histologic diagnosis of invasive adenocarcinoma of the breast

- Cedars Sinai pathology confirmation of invasive adenocarcinoma (reported or requested
and pending)

- ER, PR and HER2 negative on outside or Cedars Sinai biopsy report, where ER and PR
negative are defined as staining present in <1% 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 are not
reported the results must be requested and pending.

- Operable tumor measuring ≥1.0 cm in maximal diameter

- Any nodal status

- Multifocal and multicentric disease is permitted.

- Synchronous bilateral invasive breast cancer is permitted

- No indication of distant metastases

- Total mastectomy or lumpectomy planned

- Tumor amenable to cryoablation as determined by a study radiologist

- ECOG performance status score of 0 or 1.

- 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 ≤ 1.5 x ULN
or creatinine clearance (CrCl) ≥ 40 mL/min (if using the Cockcroft-Gault formula
below): Female CrCl = (140 - age in years) x weight in kg x 0.85 72 x serum 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 have total
bilirubin < 3.0 mg/dL)

- Negative HIV screening test

- Negative screening tests for Hepatitis B and Hepatitis C. Patients with positive
results that do not indicate true active or chronic infection may enroll after
discussion and consensus agreement by the treating physician and principal
investigator.

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

- Women of childbearing potential must have a negative serum or urine pregnancy test
(minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the
start of nivolumab

- Women must not be breastfeeding

- Willing to adhere to the study visit schedule and the prohibitions and restrictions
specified in this protocol.

- "Women of childbearing potential" is defined as any female who has experienced
menarche and who has not undergone surgical sterilization (hysterectomy or
bilateral oophorectomy) or who is not postmenopausal. Menopause is defined
clinically as 12 months of amenorrhea in a woman over 45 in the absence of other
biological or physiological causes. In addition, women under the age of 62 must
have a documented serum follicle stimulating hormone (FSH) level less than 40
mIU/mL.

Women of childbearing potential (WOCBP) receiving nivolumab and ipilimumab will be
instructed to adhere to contraception for a period of 23 weeks after the last dose of
investigational product. Men receiving nivolumab and who are sexually active with WOCBP
will be instructed to adhere to contraception for a period of 31 weeks after the last dose
of investigational product. These durations have been calculated using the upper limit of
the half-life for nivolumab (25 days) and are based on the protocol requirement that WOCBP
use contraception for 5 half-lives plus 30 days and men who are sexually active with WOCBP
use contraception for 5 half-lives plus 90 days.

Exclusion Criteria:

- Medical history and concurrent diseases

- Autoimmune disease: subjects with a documented history of inflammatory bowel
disease, including ulcerative colitis and Crohn's disease are excluded from this
study as are subjects with a history of symptomatic disease (e.g., rheumatoid
arthritis, systemic progressive sclerosis [scleroderma], Systemic Lupus
Erythematosus, autoimmune vasculitis [e.g., Wegener's Granulomatosis]). Subjects
with motor neuropathy considered of autoimmune origin (e.g., Guillain-Barre
Syndrome) are excluded from this study.

- Any underlying medical or psychiatric condition, which in the opinion of the
investigator, will make the administration of study drug hazardous or obscure the
interpretation of AEs, such as a condition associated with frequent or poorly
controlled diarrhea.

- Prohibited Treatments and/or Therapies

- Chronic use of immunosuppressants and/or systemic corticosteroids (used in the
management of cancer or non-cancer-related illnesses). Brief periods of steroid
use, for example for the management of chemotherapy-associated toxicities, are
allowed. The use of corticosteroids on study is allowed for the treatment of
immune related adverse events (irAEs) and other medical conditions including
adrenal insufficiency.

- Any non-oncology vaccine therapy used for prevention of infectious diseases
within 4 weeks prior to first dose of ipilimumab.

- Prior treatment with a CTLA4 inhibitor or PD1 inhibitor;

- Prior investigational agents within 4 weeks prior to ipilimumab/nivolumab;

- Prior therapy with any anti-cancer agents including chemotherapy, adjuvant
chemotherapy, immunosuppressive agents, surgery or radiotherapy within 4 weeks
prior to first dose of ipilimumab.