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

• ClinicalTrials.gov Identifier: NCT03546686
• Recruitment Status: Recruiting
• First Posted: June 6, 2018
• Last Update Posted: September 30, 2020
• Sponsor: Cedars-Sinai Medical Center
• Collaborator: Memorial Sloan Kettering Cancer Center
• Information provided by (Responsible Party): Heather McArthur, Cedars-Sinai Medical Center

Study Description

Brief Summary:

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 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 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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 160 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: 1:1 randomization
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Randomized Phase 2 Study of Peri-Operative Ipilimumab, Nivolumab and Cryoablation Versus Standard Peri-Operative Care in Women With Hormone Receptor-Negative, HER2-Negative Early Stage/Resectable Breast Cancer.
• Actual Study Start Date: November 12, 2019
• Estimated Primary Completion Date: May 2021
• Estimated Study Completion Date: May 2023

Arms and Interventions

Arm	Intervention/treatment
Experimental: Intervention 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 Name: 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 Name: Opdivo; Procedure: Core Biopsy/Cryoablation; MRI-guided core biopsy and cryoablation 7-10 days prior to surgery.; Procedure: Breast Surgery; Standard-of-care definitive surgery.
Active Comparator: Control Arm; Breast Surgery	Procedure: Breast Surgery; Standard-of-care definitive surgery.

Outcome Measures

Primary Outcome Measures :

1. Event-Free Survival [ Time Frame: 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 :

1. Invasive Disease-Free Survival [ Time Frame: 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
2. Distant Disease-Free Survival [ Time Frame: 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)
3. Overall Survival [ Time Frame: 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.
4. Overall Safety [ Time Frame: 36 Months ]
   Number of related adverse events based on CTCAE v.5.0

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Criteria

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 <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)
• 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.

Contacts and Locations

Contacts

Contact: Christina Abaya; 310-423-5489; Christina.Abaya@cshs.org

Locations

United States, California

Cedars Sinai Medical Center; Recruiting

Los Angeles, California, United States, 90048

Contact: Christina Abaya 310-423-5489 Christina.Abaya@cshs.org

Principal Investigator: Heather McArthur, MD, MPH

Sponsors and Collaborators

Cedars-Sinai Medical Center

Memorial Sloan Kettering Cancer Center

Investigators

• Principal Investigator: Heather McArthur, MD, MPH; Cedars-Sinai Medical Center Samuel Oschin Comprehensive Cancer Institute

More Information

• Responsible Party: Heather McArthur, Principal Investigator, Medical Director, Breast Oncology; Acting Associate Professor of Medicine, Cedars-Sinai Medical Center
• ClinicalTrials.gov Identifier: NCT03546686
• Other Study ID Numbers: IIT2018-01-McArthur-IPI
• First Posted: June 6, 2018
• Last Update Posted: September 30, 2020
• Last Verified: September 2020

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: Yes

Keywords provided by Heather McArthur, Cedars-Sinai Medical Center:

Hormone Receptor Negative; Her2- Negative; Resectable Breast Cancer; breast cancer; immunotherapy; Ipilimumab; Nivolumab; Cryoablation

Additional relevant MeSH terms:

Breast Neoplasms; Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Nivolumab; Ipilimumab; Antineoplastic Agents, Immunological; Antineoplastic Agents