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Immune Checkpoint Inhibition in Combination with Cryoablation for the Treatment of Patients Undergoing Surgery for Early Stage Triple-Negative Breast Cancer
Trial Status: active
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.
Inclusion Criteria
Women aged 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 biopsy report, where ER and PR negative are defined as staining present in =< 10% of invasive cancer cells by immunohistochemistry (IHC), and HER2-negative is defined as IHC 0-1+ or fluorescence in situ hybridization (FISH) < 2.0. If ER, PR and HER2 status are not reported the results must be requested and pending.
Operable tumor clinically measuring >= 1.0 cm.
Any nodal status allowed, including negative nodal status.
Multifocal and multicentric disease is permitted if all foci have been biopsied and also meet the criteria for triple-negative breast cancer (TNBC).
Synchronous bilateral invasive breast cancer is permitted if all foci have been biopsied and also meet the criteria for TNBC.
No indication of distant metastases.
Total mastectomy or lumpectomy planned.
Tumor amenable to cryoablation as determined by a study radiologist.
Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1.
White blood cells (WBCs) >= 2000/uL (within 15 days prior to registration).
Absolute neutrophil count (ANC) >= 1500/uL (within 15 days prior to registration).
Platelets >= 100 x 10^3/uL (within 15 days prior to registration).
Hemoglobin >= 9.0 g/dL (within 15 days prior to registration).
Serum creatinine =< 1.5 x upper limit of normal (ULN) or creatinine clearance (CrCl) >= 40 mL/min (if using the Cockcroft-Gault formula) (within 15 days prior to registration).
Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 3 x upper limit of normal (ULN) (within 15 days prior to registration).
Bilirubin =< 1.5 x ULN (except subjects with Gilbert’s syndrome, who must have total bilirubin < 3.0 mg/dL) (within 15 days prior to registration).
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, ipilimumab, and pembrolizumab 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 human chorionic gonadotropin [HCG]). Women must not be breastfeeding.
Willing to adhere to the study visit schedule and the prohibitions and restrictions specified in this protocol.
Exclusion Criteria
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 adverse events (AEs), such as a condition associated with frequent or poorly controlled diarrhea.
A history of invasive malignancy =< 5 years prior to signing informed consent except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, or ovarian cancer.
Has a known history of human immunodeficiency virus (HIV).
Has known active hepatitis B or hepatitis C.
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 4 weeks prior to first dose of ICI.
Prior investigational agents within 3 weeks prior to ICI administration.
Study sponsor and potential other locations can be found on ClinicalTrials.gov for NCT03546686.
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.
Trial PhasePhase II
Trial Typetreatment
Lead OrganizationUT Southwestern/Simmons Cancer Center-Dallas
