Renal Cell Carcinoma
Conditions
Keywords
Clear Cell, Kidney Cancer, RCC
Brief summary
The primary objective of this research is to evaluate response to systemic therapy, including anti-angiogenesis therapy and/or immune-based therapies via 18F-DCFPyL prostate-specific membrane antigen (PSMA)-based positron emission tomography/computed tomography (PET/CT) in patients with metastatic renal cell carcinoma (RCC) and to compare qualitatively with conventional imaging response criteria - Response Evaluation Criteria In Solid Tumors (RECIST 1.1) and histopathological endpoints including isolation, enumeration and staining of Circulating Tumor Cells (CTC).
Detailed description
Response of systemic therapy, including anti-angiogenesis therapy and/or immune-based therapies will be quantified using PSMA-based PET imaging using a novel agent,18F-DCFPyL, as a non-invasive imaging biomarker of tumor neovasculature to functionally monitor renal cell cancer neovasculature in patients undergoing systemic anti-angiogenesis therapy. PSMA PET will be compared with response to anti-angiogenesis therapy using conventional imaging computed tomography(CT)-based RECIST1.1 criteria as well as histopathological endpoints (tumor vascular density, immunohistochemical staining for PSMA and neovascularization (cluster of differentiation(CD)105, CD31). Whole body PSMA PET/CT scans will be obtained at baseline, following adjuvant anti- angiogenic therapy and when the patient becomes refractory to treatment. The rationale and time points for obtaining PET scans is planned with respect to the typical natural history of metastatic RCC. This project will obtain information from tumors that are responding to anti-angiogenesis therapy and those resistant to treatment.
Interventions
DRUGPSMA-based 18F-DCFPyL PET tracer for PET/CT exams
18F-DCFPyL whole body PET/CT scan administered at the following timepoints: PET1 - Prior to scheduled nephrectomy PET2 - to establish a new baseline PET before systemic therapy * PET2A - Post-surgery and prior to start of standard of care systemic therapy * PET2B - 12-16 weeks from start of first line systemic therapy (immune-based or anti-angiogenic) PET3 - If first line systemic therapy did not include anti-angiogenesis therapy and new systemic therapy does include anti-angiogenesis therapy * PET3A - Prior to start of additional anti-angiogenesis therapy * PET3B - 12-16 weeks from the start of additional anti-angiogenesis therapy PET4 - obtained at clinical progression or 2 years following initial systemic therapy
Sponsors
National Institutes of Health (NIH)
National Cancer Institute (NCI)
University of Wisconsin, Madison
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
DIAGNOSTIC
Masking
NONE
Intervention model description
This study is a single cohort study without randomization or stratification.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients diagnosed with locally advanced (\>/=cT3) or metastatic clear cell RCC as proven by biopsy. * Adults, 18 years of age or older. * Surgical candidates who have clinical indication for nephrectomy and standard-of-care biopsy of metastatic disease followed by possible standard of care systemic anti-angiogenesis based treatment regimen * Have consented to participate in the University of Wisconsin Carbone Cancer Center Biobank.
Exclusion criteria
* Patients who have received prior RCC systemic therapies * Prior history of prostate cancer * Prior history of any other malignancy within the last 2 years, other than skin basal cell or cutaneous superficial squamous cell carcinoma that has not metastasized and superficial bladder cancer * Unable to lie flat during or tolerate PET/CT * Serum creatinine \> 2 times the upper limit of normal
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Histopathological Endpoints: Neovascularization Measured by CD105 and CD31 Markers | Up to 24 months | Compare PSMA imaging to histopathological endpoints which include tumor vascular density, immunohistochemical staining for PSMA and neovascularization (CD105, CD31 markers) |
| Baseline Tumor FDG PET SUV Data by Disease Type at Baseline | Baseline | Tumor FDG PET SUV data is provided from baseline PET tumor data. Participants with baseline 18F-DCFPyL PSMA PET/CT prior to surgical nephrectomy and metastatic disease sampling were analyzed based single timepoints for PET SUVmax values of tumor uptake (primary and metastatic disease) |
| Histopathological Endpoints: Immunohistochemical Staining for PSMA | Up to 24 months | Compare PSMA imaging to histopathological endpoints which include tumor vascular density, immunohistochemical staining for PSMA and neovascularization (CD105, CD31 markers) |
| Histopathological Endpoints: Tumor Vascular Density | Up to 24 months | Compare PSMA imaging to histopathological endpoints which include tumor vascular density, immunohistochemical staining for PSMA and neovascularization (CD105, CD31 markers) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Measure Therapy Response of Patient Specific uVESSEL (a Micro Scale Organotypic Co-culture Model): Vessel Sprouting | Up to 24 months | Patient-derived uVESSEL models (from primary & metastatic sites) and incorporating patient-derived immune cells, will be tested for response to anti-angiogenic therapies including pazopanib, sunitinib, cabozantinib, and axitinib. Response will be quantified via multiple endpoints, e.g. vessel sprouting, PSMA expression, cell death. |
| Evaluate the Predictive Power and Validate the uVESSEL Model | Up to 24 months | Using the clinical, pathological and imaging endpoints, predictive models will e developed using responses to uVESSEL model above. More specifically the objective response (dichotomous endpoint of yes or no) measured using PSMA-based PET/CT will be used as a dependent variable in a logistic regression model with response to uVESSEL model from above as an independent predictor to segregate uVESSEL responses into two groups corresponding to responders and non-responders to anti-angiogenic therapies. |
| Measure Therapy Response of Patient Specific uVESSEL (a Micro Scale Organotypic Co-culture Model): PMSA Expression | Up to 24 months | Patient-derived uVESSEL models (from primary & metastatic sites) and incorporating patient-derived immune cells, will be tested for response to anti-angiogenic therapies including pazopanib, sunitinib, cabozantinib, and axitinib. Response will be quantified via multiple endpoints, e.g. vessel sprouting, PSMA expression, cell death. |
| Measure Therapy Response of Patient Specific uVESSEL (a Micro Scale Organotypic Co-culture Model): Cell Death | Up to 24 months | Patient-derived uVESSEL models (from primary & metastatic sites) and incorporating patient-derived immune cells, will be tested for response to anti-angiogenic therapies including pazopanib, sunitinib, cabozantinib, and axitinib. Response will be quantified via multiple endpoints, e.g. vessel sprouting, PSMA expression, cell death. Two subjects had data collected and were assessed. |
Countries
United States
Participant flow
Recruitment details
Participants were recruited from the University of Wisconsin Carbone Cancer Center from December 2018 to June 2021.
Participants by arm
| Arm | Count |
|---|---|
| 18F-DCFPyL Whole Body PET/CT Scan PSMA-based 18F-DCFPyL PET tracer for PET/CT exams administered at the following timepoints:
PET1 - Prior to scheduled nephrectomy
PET2 - to establish a new baseline PET before systemic therapy
* PET2A - Post-surgery and prior to start of standard of care systemic therapy
* PET2B - 12-16 weeks from start of first line systemic therapy (immune-based or anti-angiogenic)
PET3 - If first line systemic therapy did not include anti-angiogenesis therapy and new systemic therapy does include anti-angiogenesis therapy
* PET3A - Prior to start of additional anti-angiogenesis therapy
* PET3B - 12-16 weeks from the start of additional anti-angiogenesis therapy
PET4 - obtained at clinical progression or 2 years following initial systemic therapy | 5 |
| Total | 5 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Lost to Follow-up | 2 |
| Overall Study | Physician Decision | 1 |
| Overall Study | Withdrawal by Subject | 2 |
Baseline characteristics
| Characteristic | 18F-DCFPyL Whole Body PET/CT Scan |
|---|---|
| Age, Customized 30-39 years | 1 Participants |
| Age, Customized 40-49 years | 0 Participants |
| Age, Customized 50-59 years | 1 Participants |
| Age, Customized 60-69 years | 2 Participants |
| Age, Customized 70-79 years | 1 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 5 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| PET maximum SUV (SUVmax) | 6.60 SUV STANDARD_DEVIATION 3.16 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 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 | 5 Participants |
| Region of Enrollment United States | 5 participants |
| Sex: Female, Male Female | 2 Participants |
| Sex: Female, Male Male | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 5 |
| other Total, other adverse events | 0 / 5 |
| serious Total, serious adverse events | 0 / 5 |
Outcome results
Primary
Baseline Tumor FDG PET SUV Data by Disease Type at Baseline
Tumor FDG PET SUV data is provided from baseline PET tumor data. Participants with baseline 18F-DCFPyL PSMA PET/CT prior to surgical nephrectomy and metastatic disease sampling were analyzed based single timepoints for PET SUVmax values of tumor uptake (primary and metastatic disease)
Time frame: Baseline
Population: Five patients with baseline 18F-DCFPyL PSMA PET/CT prior to surgical nephrectomy and metastatic disease sampling were analyzed based on limited sample size and single timepoints for PET SUVmax values of tumor uptake (primary and metastatic disease).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 18F-DCFPyL PET/CT Scan - Primary | Baseline Tumor FDG PET SUV Data by Disease Type at Baseline | 8.78 SUV | Standard Deviation 3.35 |
| 18F-DCFPyL PET/CT Scan - Metastases | Baseline Tumor FDG PET SUV Data by Disease Type at Baseline | 5.51 SUV | Standard Deviation 2.56 |
| 18F-DCFPyL PET/CT Scan - Bone Metastases | Baseline Tumor FDG PET SUV Data by Disease Type at Baseline | 7.57 SUV | Standard Deviation 3.43 |
| 18F-DCFPyL PET/CT Scan - Soft Tissue Metastases | Baseline Tumor FDG PET SUV Data by Disease Type at Baseline | 4.63 SUV | Standard Deviation 1.7 |
Primary
Histopathological Endpoints: Immunohistochemical Staining for PSMA
Compare PSMA imaging to histopathological endpoints which include tumor vascular density, immunohistochemical staining for PSMA and neovascularization (CD105, CD31 markers)
Time frame: Up to 24 months
Population: Data were not collected for Immunohistochemical PSMA staining due to termination of funding for this study due to low accrual (see section on limitation and caveats).
Primary
Histopathological Endpoints: Neovascularization Measured by CD105 and CD31 Markers
Compare PSMA imaging to histopathological endpoints which include tumor vascular density, immunohistochemical staining for PSMA and neovascularization (CD105, CD31 markers)
Time frame: Up to 24 months
Population: Data were not collected for CD105 and CD31 neovascularization due to termination of funding for this study due to low accrual (see section on limitation and caveats).
Primary
Histopathological Endpoints: Tumor Vascular Density
Compare PSMA imaging to histopathological endpoints which include tumor vascular density, immunohistochemical staining for PSMA and neovascularization (CD105, CD31 markers)
Time frame: Up to 24 months
Population: Data were not collected for Tumor vascular density due to termination of funding for this study due to low accrual (see section on limitation and caveats).
Secondary
Evaluate the Predictive Power and Validate the uVESSEL Model
Using the clinical, pathological and imaging endpoints, predictive models will e developed using responses to uVESSEL model above. More specifically the objective response (dichotomous endpoint of yes or no) measured using PSMA-based PET/CT will be used as a dependent variable in a logistic regression model with response to uVESSEL model from above as an independent predictor to segregate uVESSEL responses into two groups corresponding to responders and non-responders to anti-angiogenic therapies.
Time frame: Up to 24 months
Population: Data were not collected to evaluate the predictive power and validation of the uVESSEL model due to termination of funding for this study due to low accrual (see section on limitation and caveats).
Secondary
Measure Therapy Response of Patient Specific uVESSEL (a Micro Scale Organotypic Co-culture Model): Cell Death
Patient-derived uVESSEL models (from primary & metastatic sites) and incorporating patient-derived immune cells, will be tested for response to anti-angiogenic therapies including pazopanib, sunitinib, cabozantinib, and axitinib. Response will be quantified via multiple endpoints, e.g. vessel sprouting, PSMA expression, cell death. Two subjects had data collected and were assessed.
Time frame: Up to 24 months
Population: A version of the models without endothelial cells was generated to evaluate tumor (only) response to therapeutics. To this end, a luminescent reagent was used to assess the amount of ATP in the models, which can be correlated to the number of live cells in the model. Measurements were taken at day 0 and at day 4 (after 72h of treatment) and normalized to account for patient-specific ATP variations. Values were acquired from at least 2 independent experiments.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 18F-DCFPyL PET/CT Scan - Primary | Measure Therapy Response of Patient Specific uVESSEL (a Micro Scale Organotypic Co-culture Model): Cell Death | Cabozantinib | 54.05 Sprout number | Standard Error 1.23 |
| 18F-DCFPyL PET/CT Scan - Primary | Measure Therapy Response of Patient Specific uVESSEL (a Micro Scale Organotypic Co-culture Model): Cell Death | Sunitinib | 28.98 Sprout number | Standard Error 4.86 |
| 18F-DCFPyL PET/CT Scan - Primary | Measure Therapy Response of Patient Specific uVESSEL (a Micro Scale Organotypic Co-culture Model): Cell Death | Vehicle Control | 148.8 Sprout number | Standard Error 6.838 |
| 18F-DCFPyL PET/CT Scan - Primary | Measure Therapy Response of Patient Specific uVESSEL (a Micro Scale Organotypic Co-culture Model): Cell Death | Pazopanib | 94.74 Sprout number | Standard Error 1.62 |
| 18F-DCFPyL PET/CT Scan - Metastases | Measure Therapy Response of Patient Specific uVESSEL (a Micro Scale Organotypic Co-culture Model): Cell Death | Vehicle Control | 70.67 Sprout number | Standard Error 3.23 |
| 18F-DCFPyL PET/CT Scan - Metastases | Measure Therapy Response of Patient Specific uVESSEL (a Micro Scale Organotypic Co-culture Model): Cell Death | Cabozantinib | 110.40 Sprout number | Standard Error 7.05 |
| 18F-DCFPyL PET/CT Scan - Metastases | Measure Therapy Response of Patient Specific uVESSEL (a Micro Scale Organotypic Co-culture Model): Cell Death | Pazopanib | 89.46 Sprout number | Standard Error 2.57 |
| 18F-DCFPyL PET/CT Scan - Metastases | Measure Therapy Response of Patient Specific uVESSEL (a Micro Scale Organotypic Co-culture Model): Cell Death | Sunitinib | 38.38 Sprout number | Standard Error 2.06 |
Secondary
Measure Therapy Response of Patient Specific uVESSEL (a Micro Scale Organotypic Co-culture Model): PMSA Expression
Patient-derived uVESSEL models (from primary & metastatic sites) and incorporating patient-derived immune cells, will be tested for response to anti-angiogenic therapies including pazopanib, sunitinib, cabozantinib, and axitinib. Response will be quantified via multiple endpoints, e.g. vessel sprouting, PSMA expression, cell death.
Time frame: Up to 24 months
Population: Data were not collected due to termination of funding for this study due to low accrual (see section on limitation and caveats).
Secondary
Measure Therapy Response of Patient Specific uVESSEL (a Micro Scale Organotypic Co-culture Model): Vessel Sprouting
Patient-derived uVESSEL models (from primary & metastatic sites) and incorporating patient-derived immune cells, will be tested for response to anti-angiogenic therapies including pazopanib, sunitinib, cabozantinib, and axitinib. Response will be quantified via multiple endpoints, e.g. vessel sprouting, PSMA expression, cell death.
Time frame: Up to 24 months
Population: Patient tumor specimen were processed and positively selected for CD31 cells, for endothelial and epithelial cell fractions. Microphysiological models were established using the two cell populations using a mold casting strategy. Models were treated with therapeutic agents after 24 hr in culture and incubated with the agent for 72hr. Imaging with confocal microscopy was used to determine individual sprout numbers. Values were acquired from at least 2 independent experiments.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 18F-DCFPyL PET/CT Scan - Primary | Measure Therapy Response of Patient Specific uVESSEL (a Micro Scale Organotypic Co-culture Model): Vessel Sprouting | Sunitinib | 2.000 Sprout number | Standard Error 1.155 |
| 18F-DCFPyL PET/CT Scan - Primary | Measure Therapy Response of Patient Specific uVESSEL (a Micro Scale Organotypic Co-culture Model): Vessel Sprouting | Pazopanib | 2.400 Sprout number | Standard Error 1.14 |
| 18F-DCFPyL PET/CT Scan - Primary | Measure Therapy Response of Patient Specific uVESSEL (a Micro Scale Organotypic Co-culture Model): Vessel Sprouting | Cabozantinib | 3.333 Sprout number | Standard Error 0.333 |
| 18F-DCFPyL PET/CT Scan - Primary | Measure Therapy Response of Patient Specific uVESSEL (a Micro Scale Organotypic Co-culture Model): Vessel Sprouting | Axitinib | NA Sprout number | — |
| 18F-DCFPyL PET/CT Scan - Primary | Measure Therapy Response of Patient Specific uVESSEL (a Micro Scale Organotypic Co-culture Model): Vessel Sprouting | Vehicle Control | 4.333 Sprout number | Standard Error 1.211 |
| 18F-DCFPyL PET/CT Scan - Metastases | Measure Therapy Response of Patient Specific uVESSEL (a Micro Scale Organotypic Co-culture Model): Vessel Sprouting | Axitinib | NA Sprout number | — |
| 18F-DCFPyL PET/CT Scan - Metastases | Measure Therapy Response of Patient Specific uVESSEL (a Micro Scale Organotypic Co-culture Model): Vessel Sprouting | Pazopanib | 15.330 Sprout number | Standard Error 3.964 |
| 18F-DCFPyL PET/CT Scan - Metastases | Measure Therapy Response of Patient Specific uVESSEL (a Micro Scale Organotypic Co-culture Model): Vessel Sprouting | Sunitinib | 13.330 Sprout number | Standard Error 2.369 |
| 18F-DCFPyL PET/CT Scan - Metastases | Measure Therapy Response of Patient Specific uVESSEL (a Micro Scale Organotypic Co-culture Model): Vessel Sprouting | Cabozantinib | 21.300 Sprout number | Standard Error 3.512 |
| 18F-DCFPyL PET/CT Scan - Metastases | Measure Therapy Response of Patient Specific uVESSEL (a Micro Scale Organotypic Co-culture Model): Vessel Sprouting | Vehicle Control | 5.364 Sprout number | Standard Error 0.927 |