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

• ClinicalTrials.gov Identifier: NCT03546686
• Recruitment Status: Recruiting
• First Posted: June 6, 2018
• Last Update Posted: December 17, 2020
• Sponsor: Cedars-Sinai Medical Center
• Collaborator: Memorial Sloan Kettering Cancer Center
• Information provided by (Responsible Party): Heather McArthur, Cedars-Sinai Medical Center

Tracking Information

• First Submitted Date: May 23, 2018
• First Posted Date: June 6, 2018
• Last Update Posted Date: December 17, 2020
• Actual Study Start Date: November 12, 2019
• Estimated Primary Completion Date: May 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: February 11, 2019)

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

Original Primary Outcome Measures (submitted: May 23, 2018)

Distant Disease-Free Survival [ Time Frame: 36 Months ]

• Time (in months) between randomization and distant recurrence (i.e. evidence of breast cancer in any anatomic site that has either been histologically confirmed or clinically diagnosed as recurrent invasive breast cancer).
• Time (in months) between randomization and second primary non-breast invasive cancer.
• Time (in months) between randomization and date of death.

Current Secondary Outcome Measures (submitted: February 11, 2019)

• 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
• 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)
• 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.
• Overall Safety [ Time Frame: 36 Months ]
  Number of related adverse events based on CTCAE v.5.0

Original Secondary Outcome Measures (submitted: May 23, 2018)

• 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 recurrance (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 brease cancer; or
  • Time (in months) between randomization and second primary non-breast invasive cancer; or
  • Time (in months) between randomization and date of death
• Disease-Free Survival [ Time Frame: 36 Months ]
  -Time (in months) between randomization and the date of the first occurrence of an invasive Disease Free Survival event including second primary non breast cancer events or contralateral or ipsilateral Ductal Carcinoma In Situ.
• 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.
• Overall Safety [ Time Frame: 36 Months ]
  Number of related adverse events based on CTCAE v.5.0

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Peri-Operative Ipilimumab+Nivolumab and Cryoablation in Women With Triple-negative Breast Cancer
• 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.
• 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.
• 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 Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Breast Cancer

Intervention

• 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
  US-guided core biopsy and cryoablation 7-10 days prior to surgery.
• Procedure: Breast Surgery
  Standard-of-care definitive surgery.

Study Arms

Experimental: Treatment Arm

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

Interventions:

• Drug: Ipilimumab
• Drug: Nivolumab
• Procedure: Core Biopsy/Cryoablation
• Procedure: Breast Surgery

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: December 14, 2020): 80
• Original Estimated Enrollment (submitted: May 23, 2018): 150
• Estimated Study Completion Date: May 2023
• Estimated Primary Completion Date: May 2021 (Final data collection date for primary outcome measure)

Eligibility Criteria

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;

Sex/Gender

• Sexes Eligible for Study: Female

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

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

• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT03546686
• Other Study ID Numbers: IIT2018-01-McArthur-IPI
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• 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

• IPD Sharing Statement: Not Provided
• Responsible Party: Heather McArthur, Cedars-Sinai Medical Center
• Study Sponsor: Cedars-Sinai Medical Center
• Collaborators: Memorial Sloan Kettering Cancer Center

Investigators

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

• PRS Account: Cedars-Sinai Medical Center
• Verification Date: December 2020