Cancer, Cancer of Liver, HCC
Conditions
Keywords
Cancer, Radiation therapy, Liver Diseases, Radiology, Interventional, Radiology
Brief summary
The study proposes low-dose Y90 microspheres for therapy planning of HCC, as an alternative to Technetium (99mTc) albumin aggregated (MAA), to be a bioidentical therapeutic Y90 surrogate marker to better predict and thus achieve optimal therapeutic dosing.
Detailed description
Hepatocellular carcinoma is a second deadliest cancer in the world with less than 20% of patients eligible for curative surgery at the time of diagnosis. Yttrium-90 (Y90) radioembolization is palliative treatment with promising result. However, one of the most important factors in the success of Y90 treatment is to ensure adequate dose of radioactive material is delivered to the tumor. The technetium-99 macroaggregated albumin (MAA) which is currently used for Y90 treatment planning and shunt study does not predict distribution of Y90 in the lungs, tumors, and liver. Therefore, accurate and personalized treatment planning cannot be performed using MAA. In this study, we are proposing using low-dose Y90 microspheres for the planning stage of the therapy to obtain an accurate estimation of distribution of Y90 therapy dose. This will in turn allow us to ensure adequate dose of Y90 is delivered to the tumor(s) while minimizing dose delivered to non-tumor liver and lungs in order to decrease the chance of treatment related toxicity to the liver and lungs.
Interventions
DEVICESIR-Spheres microspheres
SIR-Spheres® Y-90 resin microspheres consist of biocompatible polymer resin microspheres of a median diameter of 32.5 microns (range between 20 and 60 microns) loaded with yttrium-90 (beta radiation penetrating an average of 2.5 mm in tissue to destroy tumor cells). The resin microspheres are small enough to become lodged in the arterioles within the growing rim of the tumor but are too large to pass through the capillaries and into the venous system. Since yttrium-90 has a half-life of 64.1 hours, most of the radiation (94%) is delivered to the tumor over 11 days.
Sponsors
Emory University
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Adults ≥ 18 years 2. Life expectancy of 6 months or more as determined by the investigator 3. HCC confirmed by Liver Reporting & Data System (LIRADS) on MRI or CT 4. Must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as ≥20 mm (≥2 cm) with CT scan, MRI, or calipers by clinical exam. See Section 12 (Measurement of Effect) for the evaluation of measurable disease. 5. ≤3 lesions 6. Longest dimension of the largest lesion ≤7cm 7. Single lobe disease 8. No significant extrahepatic metastatic disease 9. Barcelona Clinic Liver Cancer Stage A, B or C 10. ECOG \< 2 (Appendix A) 11. Lesion(s) \<50% of liver volume 12. Bilirubin ≤ 2 mg/dL 13. Albumin ≥ 3 g/dL 14. PT/INR \< 2 15. AST/ALT ≤ 3 institutional upper limit of normal (ULN) 16. Platelet count \> 50,000/mcL 17. Lung shunt fraction of \<20% by planar MAA if dose modification results in inadequate dose delivered to the tumor(s) 18. Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial. 19. Completion of all previous therapy (including surgery, radiotherapy, chemotherapy, immunotherapy, or investigational therapy) for the treatment of cancer ≥ 12 week before the start of study therapy. Willingness and ability of the subject to comply with scheduled visits, drug administration plan, protocol-specified laboratory tests, other study procedures, and study restrictions. u. Evidence of a personally signed informed consent indicating that the subject is aware of the neoplastic nature of the disease and has been informed of the procedures to be followed, the experimental nature of the therapy, alternatives, potential risks and discomforts, potential benefits, and other pertinent aspects of study participation. v. The effects of Y90 microspheres on the developing human fetus are unknown. For this reason female of child-bearing potential (FCBP) must have a negative serum or urine pregnancy test prior to starting therapy. Winship Protocol #: RAD4784 Version Date: Aug 22, 2019 20 \| P a g e w. FCBP and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of \[IND Agent\] administration. A female of childbearing potential (FCBP) is a sexually mature woman who: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months
Exclusion criteria
* An individual who does not meet all the inclusion criteria in section.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Lung Shunt Fraction (LSF) Ratio | Baseline | Y-90 radioembolization treatment requires estimating the activity shunted from the liver to the lungs, referred to as a lung shunt fraction (LSF). It is expressed in ratios, with higher ratio meaning a higher transit of Y-90 to the lungs (worse outcome) and lower ratio, lower transit of Y-90 to the lungs (better outcome). |
| Tumor to Normal Liver Activity Ratio (TNR) | Baseline | The ratios of the tumor-to-normal liver parenchymal radioactivity uptake count will be measured. TNR values will be calculated by dividing the mean count of the tumorous volume of interest (VOI) by the mean count of normal liver. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Tumor Response Using Imaging Modified Response Criteria in Solid Tumors (m-RECIST) Post Y90 Embolization | 6 months post intervention | To identify tumor dose response threshold (TDRT) using Imaging Modified Response Criteria in Solid Tumors (m-RECIST), that is a method for measuring treatment response and measure of antitumor activity of cytotoxic drugs. This is measured using imaging: CT or MRI. The overall response is a combination of responses in each category: complete response (disappearance of any intramural arterial enhancement in all target lesions), partial response (at least 30% decrease in the sum of the diameters of viable target lesions), stable disease (any cases that do not qualify for either partial response or progressive disease) or progressive disease (an increase of at least 20% in the sum of the diameters of viable, enhancing target lesions, taking as a reference the smallest sum of the diameters of viable target lesions recorded since treatment started). |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Technetium-99m Macroaggregated Albumin (99mTc-MAA)/ Second Mapping With Low-dose Y90 Patients will undergo standard of care mapping study with 99TC-MAA to plan for Y90 radioembolization therapy. Following MAA, non-standard of care, intervention will be to do a second mapping study using SIR-spheres microspheres with low-dose Y90 (15 mCi) before the therapeutic Y90 radioembolization.
SIR-Spheres microspheres: SIR-Spheres® Y-90 resin microspheres consist of biocompatible polymer resin microspheres of a median diameter of 32.5 microns (range between 20 and 60 microns) loaded with yttrium-90 (beta radiation penetrating an average of 2.5 mm in tissue to destroy tumor cells). The resin microspheres are small enough to become lodged in the arterioles within the growing rim of the tumor but are too large to pass through the capillaries and into the venous system. Since yttrium-90 has a half-life of 64.1 hours, most of the radiation (94%) is delivered to the tumor over 11 days. | 30 |
| Total | 30 |
Baseline characteristics
| Characteristic | Technetium-99m Macroaggregated Albumin (99mTc-MAA)/ Second Mapping With Low-dose Y90 |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 27 Participants |
| Age, Categorical Between 18 and 65 years | 3 Participants |
| Age, Continuous | 66.4 years STANDARD_DEVIATION 6.6 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 29 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants |
| Race (NIH/OMB) Black or African American | 11 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 17 Participants |
| Region of Enrollment United States | 30 participants |
| Sex: Female, Male Female | 3 Participants |
| Sex: Female, Male Male | 27 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 1 / 30 |
| other Total, other adverse events | 23 / 30 |
| serious Total, serious adverse events | 1 / 30 |
Outcome results
Primary
Lung Shunt Fraction (LSF) Ratio
Y-90 radioembolization treatment requires estimating the activity shunted from the liver to the lungs, referred to as a lung shunt fraction (LSF). It is expressed in ratios, with higher ratio meaning a higher transit of Y-90 to the lungs (worse outcome) and lower ratio, lower transit of Y-90 to the lungs (better outcome).
Time frame: Baseline
Population: Participants underwent standard of care and then underwent second mapping with low dose Y90 intervention.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Technetium-99m Macroaggregated Albumin (99mTc-MAA) | Lung Shunt Fraction (LSF) Ratio | 5.68 Ratio | Standard Deviation 3.12 |
| Second Mapping With Low-dose Y90 | Lung Shunt Fraction (LSF) Ratio | 5.79 Ratio | Standard Deviation 2.08 |
Primary
Tumor to Normal Liver Activity Ratio (TNR)
The ratios of the tumor-to-normal liver parenchymal radioactivity uptake count will be measured. TNR values will be calculated by dividing the mean count of the tumorous volume of interest (VOI) by the mean count of normal liver.
Time frame: Baseline
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Technetium-99m Macroaggregated Albumin (99mTc-MAA) | Tumor to Normal Liver Activity Ratio (TNR) | 2.67 Ratio | Standard Deviation 1.67 |
| Second Mapping With Low-dose Y90 | Tumor to Normal Liver Activity Ratio (TNR) | 2.75 Ratio | Standard Deviation 1.2 |
Secondary
Number of Participants With Tumor Response Using Imaging Modified Response Criteria in Solid Tumors (m-RECIST) Post Y90 Embolization
To identify tumor dose response threshold (TDRT) using Imaging Modified Response Criteria in Solid Tumors (m-RECIST), that is a method for measuring treatment response and measure of antitumor activity of cytotoxic drugs. This is measured using imaging: CT or MRI. The overall response is a combination of responses in each category: complete response (disappearance of any intramural arterial enhancement in all target lesions), partial response (at least 30% decrease in the sum of the diameters of viable target lesions), stable disease (any cases that do not qualify for either partial response or progressive disease) or progressive disease (an increase of at least 20% in the sum of the diameters of viable, enhancing target lesions, taking as a reference the smallest sum of the diameters of viable target lesions recorded since treatment started).
Time frame: 6 months post intervention
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Technetium-99m Macroaggregated Albumin (99mTc-MAA) | Number of Participants With Tumor Response Using Imaging Modified Response Criteria in Solid Tumors (m-RECIST) Post Y90 Embolization | Partial tumor response | 3 Count of participants |
| Technetium-99m Macroaggregated Albumin (99mTc-MAA) | Number of Participants With Tumor Response Using Imaging Modified Response Criteria in Solid Tumors (m-RECIST) Post Y90 Embolization | Stable disease | 6 Count of participants |
| Technetium-99m Macroaggregated Albumin (99mTc-MAA) | Number of Participants With Tumor Response Using Imaging Modified Response Criteria in Solid Tumors (m-RECIST) Post Y90 Embolization | Progression of disease | 0 Count of participants |
| Technetium-99m Macroaggregated Albumin (99mTc-MAA) | Number of Participants With Tumor Response Using Imaging Modified Response Criteria in Solid Tumors (m-RECIST) Post Y90 Embolization | Complete tumor response | 23 Count of participants |