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

Sponsor

Heather McArthur (Other)

Overall Status

Recruiting

CT.gov ID

NCT03546686

Collaborator

Memorial Sloan Kettering Cancer Center (Other)

Enrollment

Locations

Arm

78.6

Anticipated Duration (Months)

Patients Per Site

0.5

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Breast Cancer	Drug: Ipilimumab Drug: Nivolumab Procedure: Core Biopsy/Cryoablation Procedure: Breast Surgery	Phase 2

Detailed Description

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

80 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Single Arm Phase 2 Study of Peri-Operative Ipilimumab, Nivolumab and Cryoablation in Women With Hormone Receptor-Negative, HER2-Negative Early Stage/Resectable Breast Cancer.

Actual Study Start Date :

Nov 12, 2019

Anticipated Primary Completion Date :

Jun 1, 2024

Anticipated Study Completion Date :

Jun 1, 2026

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treatment Arm Ipilimumab + Nivolumab + Core Biopsy/Cryoablation + Breast Surgery +Post Surgery Nivolumab	Drug: Ipilimumab Patients will receive ipilimumab 1-5 days prior to core biopsy and cryoablation. Other Names: Yervoy Drug: Nivolumab Patients will receive nivolumab 1-5 days prior to core biopsy and cryoablation and every 2 weeks post surgery for 3 additional doses Other Names: Opdivo Procedure: Core Biopsy/Cryoablation US-guided core biopsy and cryoablation 7-10 days prior to surgery. Procedure: Breast Surgery Standard-of-care definitive surgery.

Arm

Intervention/Treatment

Experimental: Treatment Arm

Ipilimumab + Nivolumab + Core Biopsy/Cryoablation + Breast Surgery +Post Surgery Nivolumab

Drug: Ipilimumab

Patients will receive ipilimumab 1-5 days prior to core biopsy and cryoablation.

Other Names:

Yervoy

Drug: Nivolumab

Patients will receive nivolumab 1-5 days prior to core biopsy and cryoablation and every 2 weeks post surgery for 3 additional doses

Other Names:

Opdivo

Procedure: Core Biopsy/Cryoablation

US-guided core biopsy and cryoablation 7-10 days prior to surgery.

Procedure: Breast Surgery

Standard-of-care definitive surgery.

Outcome Measures

Primary Outcome Measures

Event-Free Survival [36 Months]
Time (in months) between randomization and first occurrence of progression of disease that precludes surgery Time (in months) between randomization and first occurrence local or distant disease recurrence Time (in months) between randomization and date of death attributable to any cause including breast cancer, non-breast cancer, or unknown cause

Secondary Outcome Measures

Invasive Disease-Free Survival [36 Months]
Time (in months) between randomization and ipsilateral invasive breast tumor recurrence (i.e. an invasive breast cancer involving the same breast parenchyma as the original primary lesion); or Time (in months) between randomization and ipsilateral local-regional invasive breast cancer (i.e. an invasive breast cancer in the axilla, regional lymph nodes, chest wall and/or skin of the ipsilateral breast); or Time (in months) between randomization and distant recurrence (i.e. evidence of breast cancer in any anatomic site - other than the two abovementioned sites - that has either been histologically confirmed or clinically diagnosed as recurrent invasive breast cancer); or Time (in months) between randomization and contralateral invasive breast cancer; or Time (in months) between randomization and second primary non-breast invasive cancer; or Time (in months) between randomization and date of death
Distant Disease-Free Survival [36 Months]
-Time (in months) between randomization and the date of the first occurrence of distant recurrence (i.e. evidence of breast cancer in any anatomic site - other than local regional sites - that has either been histologically confirmed or clinically diagnosed as recurrent invasive breast cancer)
Overall Survival [36 Months]
-Time (in months) between randomization and death attributable to any cause. Patients who are alive, including lost to follow-up, at the time of the analysis will be censored at the last known alive date.
Overall Safety [36 Months]
Number of related adverse events based on CTCAE v.5.0

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

Female

Accepts Healthy Volunteers:

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
Has an active autoimmune disease that has required systemic treatment in the past 2 years (i.e., with use of disease modifying agents, corticosteroids, or immunosuppressive drugs). Note: Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment.
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 live 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