This phase II trial tests how well immune checkpoint inhibition in combination with cryoablation prior to standard of care surgery works in treating patients with early stage triple-negative breast cancer that can be removed by surgery (resectable). Immunotherapy with monoclonal antibodies, such as ipilimumab and nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Cryoablation is a procedure in which an extremely cold liquid or an instrument called a cryoprobe is used to freeze and destroy abnormal tissue. Cryoablation may be used to treat certain types of cancer and some conditions that may become cancer. Giving ipilimumab and nivolumab with cryoablation prior to standard of care surgery may be more effective at treating patients with early stage triple-negative breast cancer than surgery alone.
Study sponsor and potential other locations can be found on ClinicalTrials.gov for NCT03546686.
PRIMARY OBJECTIVE:
I. To determine the impact of pre-operative cryoablation with ICI on 3-year event free survival (EFS), in women with residual hormone receptor negative (estrogen receptor [ER] and progesterone receptor [PR] =< 10%), HER2-negative (“triple negative”) resectable breast cancer after taxane-based neoadjuvant chemotherapy.
SECONDARY OBJECTIVES:
I. To determine the impact of the intervention on invasive disease-free survival (IDFS), distant disease-free survival (DDFS), and overall survival (OS).
II. To describe the safety/tolerability/toxicity of the intervention.
EXPLORATORY OBJECTIVES:
I. To characterize the immunologic effect of peri-operative cryoablation (cryo) and ICI administration in peripheral blood, intratumorally, and on the microbiome through serial blood, tissue, and stool collection, for example, by:
Ia. Describing changes in peripheral blood CD3+, CD4+, CD8+, or regulatory (CD4+FOXP3+) T-cells by flow cytometry over time;
Ib. Characterizing the effect of the intervention on peripheral levels of Th1 and Th2-type cytokines over time;
Ic. Characterizing tumor infiltrating lymphocytes (TILs) isolated from tumor biopsies and resection specimens using flow cytometry;
Id. Describing T-cell clonality and diversity by T-cell receptor deoxyribonucleic acid (DNA) deep sequencing in tumor and peripherally;
Ie. Describing PD-L1 expression at baseline and in response to therapy (applying Salgado criteria, Dieci 2017);
If. Describing peripheral absolute lymphocyte count (ALC) at baseline and changes in response to the intervention (week 9 ALC and on-therapy ALC trend have been associated with clinical benefit to ipilimumab; Ku 2010, Postow 2013);
Id. Assessing changes in the microbiome during the study period.
II. To correlate clinical outcomes with exploratory correlates wherever feasible, in order to explore potential predictive biomarkers of clinical efficacy or toxicity.
OUTLINE:
Patients receive ipilimumab intravenously (IV) and nivolumab IV on days -5, -4, -3, -2, -1. Patients undergo cryoablation 7-10 days prior to standard of care (SOC) surgery. Patients may receive pembrolizumab IV 1-20 days prior to cryoablation and 3 weeks after surgery for 9 cycles per SOC. Patients then receive nivolumab every 2 weeks (Q2W) starting 3 weeks after surgery. Patients undergo collection of blood samples at baseline, at cryoablation, at surgery, 2 and 6 weeks, and 1 year after surgery. Patients may also undergo fecal sample collection at baseline, cryoablation, at surgery, and at cycle 2 day 1 and cycle 4 day 1, and 1 year after surgery. Patients also undergo ultrasound or magnetic resonance imaging (MRI)-guided tissue biopsy 7 to 10 days prior to SOC surgery.
After completion of study treatment, patients are followed up every 3 months for 36 months, and then every 6 months until month 60.
Lead OrganizationUT Southwestern/Simmons Cancer Center-Dallas
Principal InvestigatorHeather Lynn McArthur
