Perflutren Protein-Type A Microspheres and Contrast-Enhanced Ultrasound in Improving Response to Radioembolization Therapy in Patients With Liver Cancer

Study Overview
=================
Brief Summary
-----------------
This phase II trial studies how well perflutren protein-type A microspheres and contrast-enhanced ultrasound work in improving response to radioembolization therapy in patients with liver cancer. Ultrasound contrast agents, such as perflutren protein-type A microspheres, use gas microbubbles to improve image quality. Using contrast-enhanced ultrasound imaging will pop these microbubbles and cause tumors to become more sensitive to radiation therapies.

Detailed Description
-----------------
PRIMARY OBJECTIVE: I. Characterize the ability of localized ultrasound contrast agent destruction to improve hepatocellular carcinoma (HCC) response to yttrium Y-90 (Y90) radioembolization. SECONDARY OBJECTIVE: I. Determine if contrast-enhanced ultrasound estimated tumor perfusion can reliably predict HCC response to radioembolization 1-14 days post treatment. OUTLINE: Patients are randomized to 1 of 2 groups. GROUP I: Patients receive perflutren protein-type A microspheres intravenously (IV) over 10 minutes and undergo contrast-enhanced ultrasound (CEUS) over 60 minutes at 1-6 hours and at approximately 7 and 14 days after yttrium Y-90 radioembolization. GROUP II: Patients undergo standard of care yttrium Y-90 radioembolization. After completion of study treatment, patients are followed up at 1 month and at 3-4 months.

Official Title
-----------------
Ultrasound Microbubble Destruction and Perfusion Quantification for Improving Radioembolization Therapy of Hepatocellular Carcinoma

Conditions
-----------------
Hepatocellular Carcinoma

Intervention / Treatment
-----------------
* Procedure: Yttrium-90 Microsphere Radioembolization
* Drug: Perflutren Protein-Type A Microspheres
* Procedure: Dynamic Contrast-Enhanced Ultrasound Imaging


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Be scheduled for sub-lobar radioembolization therapy of a previously untreated HCC mass < 6 cm visible on grayscale ultrasound Be medically stable If a female of child-bearing age, have a negative pregnancy test prior to each ultrasound exam Have signed informed consent to participate in the study Exclusion Criteria: Females who are pregnant or nursing Patients who are medically unstable, patients who are seriously or terminally ill, and patients whose clinical course is unpredictable; for example: Patients on life support or in a critical care unit Patients with unstable occlusive disease (e.g., crescendo angina) Patients with clinically unstable cardiac arrhythmias, such as recurrent ventricular tachycardia Patients with uncontrolled congestive heart failure (New York heart Association [NYHA] class IV) Patients with recent cerebral hemorrhage Patients with known sensitivities to albumin, blood, or blood products Patients with known hypersensitivity to perflutren Patients with known cardiac shunts Patients with known congenital heart defects Patients with severe emphysema, pulmonary vasculitis, or a history of pulmonary embolism Patients with respiratory distress syndrome Patients with a history of bleeding disorders Patients with bilirubin levels > 2 mg/dL

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
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group I (perflutren protein-type A microspheres, CEUS)<br>Patients receive perflutren protein-type A microspheres IV over 10 minutes and undergo CEUS over 60 minutes at 1-6 hours and at approximately 7 and 14 days after yttrium Y-90 radioembolization. | Procedure: Yttrium-90 Microsphere Radioembolization<br>* Undergo standard of care Y-90 radioembolization<br>* Other names: Yttrium-90 Radioembolization;Drug: Perflutren Protein-Type A Microspheres<br>* Given IV.<br>* Other names: Optison;Procedure: Dynamic Contrast-Enhanced Ultrasound Imaging<br>* Undergo CEUS<br>|
| Active Comparator: Group II (standard of care)<br>Patients undergo standard of care yttrium Y-90 radioembolization. | Procedure: Yttrium-90 Microsphere Radioembolization<br>* Undergo standard of care Y-90 radioembolization<br>* Other names: Yttrium-90 Radioembolization;|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Treatment response to yttrium Y-90 radioembolization | Measured using the modified Response Evaluation Criteria in Solid Tumors. Will be tested with a non-parametric Mann- Whitney U-test of the difference in response distributions between control (radioembolization alone) and experimental group (ultrasound-triggered microbubble destruction [UTMD] + radioembolization). The outcome variable in this analysis, the modified Response Evaluation Criteria in Solid Tumors (mRECIST) score, is treated as an ordinal variable in this analysis. | Up to 4 months | 
| Tumor perfusion measured by contrast-enhanced ultrasound between ultrasound-triggered microbubble destruction pulses | Perfusion will be characterized in terms of contrast replenishment time intensity curves fit with a 2-parameter exponential recovery curve. The relationship between the normalized perfusion values from this image processing and the patients' subsequent mRECIST scores in the UTMD + radioembolization group will be evaluated with Spearman's rank order correlation. | Up to 14 days |