High-Intensity Focused Ultrasound and Pembrolizumab in Treating Patients with Metastatic or Unresectable Breast Cancer

Inclusion Criteria

• Subjects with histologically confirmed metastatic or unresectable breast cancer (male or female)
• Be willing and able to provide written informed consent/assent for the trial
• Must be determined to have metastatic or unresectable disease, as determined by treating physician; (must have at least evaluable disease, but does not need to be measurable disease by RECIST 1.1)
• Any receptor status (estrogen receptor, progesterone receptor, HER2 receptor); patients who are hormone receptor (HR)+ should also no longer be candidates for hormonal-based therapy; patients who are HER2+ should have progressed on or no longer be candidates for available HER2 directed therapy; hormonal therapy must be stopped prior to day 1 of treatment
• Patients must have had at least one prior line of therapy for breast cancer in the metastatic/unresectable setting. Patients demonstrating a rising tumor marker during a line of therapy or demonstrating intolerance of a standard or investigational therapy meet this criteria (includes endocrine or chemotherapy or targeted therapy).
• Patients must have an accessible lesion in the breast/chest wall/axilla which has not been previously thermally ablated; prior breast irradiation is acceptable if the lesion has recurred or grown following radiation
• Subjects must have at least one target lesion in breast/chest wall/axilla which is amenable to application of high intensity focused ultrasound: * The distance from the skin: A targetable portion of the tumor must be >= 5 mm from the skin * The rib cage should not be in the prefocal ultrasound path or behind the target area of the lesion (minimum distance from the posterior aspect of the target area to rib cage must be at least 10 mm) * Subject’s tumor must be larger than 9 mm in the anterior-posterior dimension (measured by ultrasound) * Subject’s tumor must be greater than or equal to 0.3 cubic centimeters
• Subject must be >= 18 years of age on day of signing informed consent
• Be willing to provide tissue from a newly obtained core or excisional biopsy of a tumor lesion
• Have a performance status of 0-2 on the Eastern Cooperative Oncology Group (ECOG) performance scale
• Absolute neutrophil count (ANC) >= 1,500/mcL
• Platelets >= 100,000/mcL
• Hemoglobin >= 9 g/dL or >= 5.6 mmol/L without transfusion or erythropoietin (EPO) dependency (within 7 days of assessment)
• Serum creatinine =< 1.5 X upper limit of normal (ULN) OR measured or calculated creatinine clearance (glomerular filtration rate [GFR] can also be used in place of creatinine or creatinine clearance [CrCl]) >= 60 mL/min for subject with creatinine levels > 1.5 X institutional ULN
• Serum total bilirubin =< 1.5 X ULN OR direct bilirubin =< ULN for subjects with total bilirubin levels > 1.5 ULN
• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 X ULN OR =< 5 X ULN for subjects with liver metastases
• Albumin >= 2.5 mg/dL
• International normalized ratio (INR) or prothrombin time (PT) =< 1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or partial thromboplastin time (PTT) is within therapeutic range of intended use of anticoagulants
• Activated partial thromboplastin time (aPTT) =< 1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants
• Female subject of childbearing potential should have a negative urine or serum pregnancy within 72 hours prior to receiving the first dose of study medication or study indicated ultrasound treatment; if the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
• Female subjects of childbearing potential must be willing to use an adequate method of contraception, for the course of the study through 120 days after the last dose of study medication * Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject
• Male subjects of childbearing potential must agree to use an adequate method of contraception, starting with the first dose of study therapy through 120 days after the last dose of study therapy * Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject

Exclusion Criteria

• Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of treatment
• Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment; systemic corticosteroids of less than 10 mg per day of prednisone (or equivalent) are allowed; topical corticosteroids are acceptable, including steroids with very low solubility administered nasally for local effects only (e.g. Nasonex)
• Has a known history of active TB (Bacillus tuberculosis)
• Hypersensitivity to pembrolizumab or any of its excipients
• Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study day 1 or who has not recovered (i.e., =< grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier
• Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study day 1 or who has not recovered (i.e., =< grade 1 or at baseline) from adverse events due to a previously administered agent * Note: Subjects with =< grade 2 neuropathy are an exception to this criterion and may qualify for the study * Note: If subject received major surgery or radiation, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy * Note: anti-estrogen therapy must be stopped prior to study day 1
• Has a known additional malignancy that is progressing or requires active treatment; exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer
• Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging within four weeks prior to registration and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment; this exception does not include carcinomatous meningitis which is excluded regardless of clinical stability
• Has 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); replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment
• Has a history of (non-infectious) pneumonitis/interstitial lung disease that required steroids or current pneumonitis/interstitial lung disease
• Has an active infection requiring systemic therapy
• Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject’s participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator
• Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial
• Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment
• Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent within the prior 24 weeks
• Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies)
• Has known active hepatitis B (e.g., hepatitis B surface antigen [HBsAg] reactive) or hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is detected)
• Has received a live vaccine or live attenuated vaccine within 30 days of planned start of study therapy. Administration of killed vaccines is allowed. * Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist) are live attenuated vaccines, and are not allowed
• HIFU must not be applied to a breast with an implant. A region outside of the breast may be targeted as long as the targeted area is at least 10mm away from an implant.