Peri-Operative Ipilimumab+Nivolumab and Cryoablation in Women With Triple-negative Breast Cancer
Peri-Operative Ipilimumab+Nivolumab and Cryoablation in Women With Triple-negative Breast Cancer
The purpose of this study is to determine the impact of pre-operative cryoablation,
 ipilimumab and nivolumab on on 3-year Event Free Survival (EFS), in women with residual
 hormone receptor negative, HER2-negative ("triple negative") resectable breast cancer after
 taxane-based neoadjuvant chemotherapy.
The purpose of this study is to determine the impact of pre-operative cryoablation,
 ipilimumab and nivolumab 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 treated with
 tumor cryoablation and 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 carcinoma of the breast

 -  Pathology confirmation of invasive carcinoma (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 ≤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 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)

 -  No history of known HIV

 -  No history of known active hepatitis B or hepatitis C

 -  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)

 -  Women must not be breastfeeding

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

 -  Prior checkpoint blockade administration is permitted with a washout period of 3 weeks

 -  "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.

 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 3 weeks prior to first dose of ipilimumab.

 -  Prior investigational agents within 3 weeks prior to ipilimumab/nivolumab;