Focused Ultrasound and Pembrolizumab in Metastatic Breast Cancer

Study Overview
=================
Brief Summary
-----------------
This pilot study evaluates the use of high-intensity focused ultrasound (HIFU) combined with pembrolizumab in patients with metastatic breast cancer. One-half of participants will be randomized to receive the first dose of pembrolizumab after HIFU and one-half of participants will be randomized to receive their first dose of pembrolizumab before HIFU.

Official Title
-----------------
Focused Ultrasound Therapy to Augment Antigen Presentation and Immune-Specificity of Checkpoint Inhibitor Therapy With Pembrolizumab in Metastatic Breast Cancer

Conditions
-----------------
Breast Cancer

Intervention / Treatment
-----------------
* Drug: Pembrolizumab
* Device: High-intensity focused ultrasound (HIFU)


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria (summary): Histologically confirmed metastatic or unresectable breast cancer Any receptor status (estrogen receptor, progesterone receptor, HER2 receptor). Patients who are 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 setting. 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. Patients must agree to use an adequate method of contraception for the course of the study through 120 days after the last dose of study medication. Patients must have at least one target lesion in breast/chest wall/axilla which is amenable to application of high intensity focused ultrasound: Patients must be willing to provide tissue from a newly obtained core or excisional biopsy of a tumor lesion. Performance status of 0 or 1 on the ECOG Performance Scale. Adequate organ function Exclusion Criteria (summary): Patients currently participating and receiving study therapy or patients who have 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. Patients with a diagnosis of immunodeficiency, patients receiving systemic steroid therapy or, patients who have received any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment. Patients with a known history of active Tuberculosis Hypersensitivity to pembrolizumab or any of its excipients Prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study Day 1. Patients who have not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier are excluded. Prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study Day 1. Patients who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to a previously administered agent. 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. Known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Active autoimmune disease that has required systemic treatment in the past 2 years. History of (non-infectious) pneumonitis that required steroids or current pneumonitis. Active infection requiring systemic therapy. Pregnancy Prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent within the prior 24 weeks. Known history of Human Immunodeficiency Virus (HIV) Receipt of a live vaccine within 30 days of planned start of study therapy. 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.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Pilot, 2-arm randomized study
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A: 1st dose of pembrolizumab after HIFU<br>Pembrolizumab (200 mg) administered intravenously, days 22, 43, 64, followed by day 1 of each ensuing 3 -week cycle. Focused ultrasound tumor ablation day 15. High-intensity focused ultrasound ablation will target 50% of the tumor, up to 3 cubic centimeters. | Drug: Pembrolizumab<br>* Pembrolizumab (200 mg)<br>* Other names: Keytruda;Device: High-intensity focused ultrasound (HIFU)<br>* Ablation will target 50% of the tumor, up to 3 cubic centimeters<br>|
| Experimental: Arm B: 1st dose of pembrolizumab before HIFU<br>Pembrolizumab (200 mg) intravenously, days 1, 22, 43, 64, followed by day 1 of each ensuing 3 -week cycle. Focused ultrasound tumor ablation day 15. High-intensity focused ultrasound ablation will target 50% of the tumor, up to 3 cubic centimeters. | Drug: Pembrolizumab<br>* Pembrolizumab (200 mg)<br>* Other names: Keytruda;Device: High-intensity focused ultrasound (HIFU)<br>* Ablation will target 50% of the tumor, up to 3 cubic centimeters<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in tumor infiltrating lymphocytes | Change in proportion of CD8+ tumor infiltrating lymphocytes (ration CD8+/CD4+) in the primary ablation zone | baseline and week 4 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse event profile of pembrolizumab and HIFU | Toxicities from the combination of pembrolizumab and HIFU | From date of randomization through 30 days following cessation of treatment | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
breast cancer, pembrolizumab, focused ultrasound, immunotherapy