Hepatocellular Carcinoma
Conditions
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.
Interventions
Undergo standard of care Y-90 radioembolization
Given IV.
Undergo CEUS
Sponsors
National Institutes of Health (NIH)
National Cancer Institute (NCI)
Thomas Jefferson University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Treatment Response to Yttrium Y-90 Radioembolization | Up to 4 months | 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. Tumor response assessed using modified Response Evaluation Criteria in Solid Tumors (mRECIST). The mRECIST scale includes four ordered categories: * Complete Response (best outcome) * Partial Response * Stable Disease * Progressive Disease (worst outcome) |
| Tumor Perfusion Measured by Contrast-enhanced Ultrasound Between Ultrasound-triggered Microbubble Destruction Pulses | Up to 14 days | 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. Tumor perfusion measured as fractional vascularity (%) using contrast-enhanced ultrasound (CEUS). Values range from 0% (no perfusion) to 100% (maximal perfusion). |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Group I (Perflutren Protein-type A Microspheres, CEUS) 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.
Yttrium-90 Microsphere Radioembolization: Undergo standard of care Y-90 radioembolization
Perflutren Protein-Type A Microspheres: Given IV.
Dynamic Contrast-Enhanced Ultrasound Imaging: Undergo CEUS | 52 |
| Group II (Standard of Care) Patients undergo standard of care yttrium Y-90 radioembolization.
Yttrium-90 Microsphere Radioembolization: Undergo standard of care Y-90 radioembolization | 52 |
| Total | 104 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Deemed screen fail because he had no arteries to access during flow study | 0 | 1 |
| Overall Study | Lost to Follow-up | 0 | 1 |
| Overall Study | Withdrawal by Subject | 4 | 0 |
Baseline characteristics
| Characteristic | Group I (Perflutren Protein-type A Microspheres, CEUS) | Group II (Standard of Care) | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 36 Participants | 38 Participants | 74 Participants |
| Age, Categorical Between 18 and 65 years | 16 Participants | 14 Participants | 30 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 2 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 50 Participants | 50 Participants | 100 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 5 Participants | 5 Participants | 10 Participants |
| Race (NIH/OMB) Black or African American | 8 Participants | 7 Participants | 15 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 2 Participants | 4 Participants |
| Race (NIH/OMB) White | 37 Participants | 38 Participants | 75 Participants |
| Sex: Female, Male Female | 20 Participants | 8 Participants | 28 Participants |
| Sex: Female, Male Male | 32 Participants | 44 Participants | 76 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 52 | 0 / 52 |
| other Total, other adverse events | 4 / 52 | 2 / 52 |
| serious Total, serious adverse events | 0 / 52 | 0 / 52 |
Outcome results
Primary
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. Tumor response assessed using modified Response Evaluation Criteria in Solid Tumors (mRECIST). The mRECIST scale includes four ordered categories: * Complete Response (best outcome) * Partial Response * Stable Disease * Progressive Disease (worst outcome)
Time frame: Up to 4 months
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Group I (Perflutren Protein-type A Microspheres, CEUS) | Treatment Response to Yttrium Y-90 Radioembolization | Complete Response | 25 Participants |
| Group I (Perflutren Protein-type A Microspheres, CEUS) | Treatment Response to Yttrium Y-90 Radioembolization | Partial Response | 17 Participants |
| Group I (Perflutren Protein-type A Microspheres, CEUS) | Treatment Response to Yttrium Y-90 Radioembolization | Progressive Disease | 4 Participants |
| Group I (Perflutren Protein-type A Microspheres, CEUS) | Treatment Response to Yttrium Y-90 Radioembolization | Stable Disease | 2 Participants |
| Group II (Standard of Care) | Treatment Response to Yttrium Y-90 Radioembolization | Progressive Disease | 3 Participants |
| Group II (Standard of Care) | Treatment Response to Yttrium Y-90 Radioembolization | Partial Response | 17 Participants |
| Group II (Standard of Care) | Treatment Response to Yttrium Y-90 Radioembolization | Stable Disease | 17 Participants |
| Group II (Standard of Care) | Treatment Response to Yttrium Y-90 Radioembolization | Complete Response | 13 Participants |
Primary
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. Tumor perfusion measured as fractional vascularity (%) using contrast-enhanced ultrasound (CEUS). Values range from 0% (no perfusion) to 100% (maximal perfusion).
Time frame: Up to 14 days
Population: Contrast-enhanced ultrasound (study intervention) is only collected from patients in Arm 1.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Group I (Perflutren Protein-type A Microspheres, CEUS) | Tumor Perfusion Measured by Contrast-enhanced Ultrasound Between Ultrasound-triggered Microbubble Destruction Pulses | Viable Tumors | 62 percentage of tumor vascularity | Standard Deviation 28 |
| Group I (Perflutren Protein-type A Microspheres, CEUS) | Tumor Perfusion Measured by Contrast-enhanced Ultrasound Between Ultrasound-triggered Microbubble Destruction Pulses | Non-Viable Tumors | 38 percentage of tumor vascularity | Standard Deviation 24 |