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18F-FSPG PET in Imaging Patients With Liver Cancer Before Undergoing Surgery or Transplant

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ClinicalTrials.gov Identifier: NCT02379377
Recruitment Status : Not yet recruiting
First Posted : March 4, 2015
Last Update Posted : September 10, 2021
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
M.D. Anderson Cancer Center

Tracking Information
First Submitted Date  ICMJE February 6, 2015
First Posted Date  ICMJE March 4, 2015
Last Update Posted Date September 10, 2021
Estimated Study Start Date  ICMJE October 1, 2021
Estimated Primary Completion Date May 31, 2024   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 24, 2020)
  • 18F-FSPG PET standardized uptake value (SUV) [ Time Frame: Within 4 weeks of standard-of-care imaging, within 4 weeks of liver resection surgery, within 12 months of orthotopic liver transplant and prior to therapy ]
    The Standardized Uptake Value (SUV) for 18F-FSPG PET images will be determined in the hepatocellular carcinoma (HCC) tumor lesions, non-HCC liver tumors (benign), and background liver (normal tissue). These metrics include SUVmax, SUVpeak, or SUVmean and are common PET imaging measures.
  • 11C-acetate standardized uptake value (SUV) [ Time Frame: Within 4 weeks of standard-of-care imaging, within 4 weeks of liver resection surgery, within 12 months of orthotopic liver transplant and prior to therapy ]
    The Standardized Uptake Value (SUV) for 11C-acetate PET images will be determined in the tumor lesions and background liver (normal tissue). These metrics include SUVmax, SUVpeak, or SUVmean and are common PET imaging measures.
  • 18F-FDG standardized uptake value (SUV) [ Time Frame: Within 4 weeks of standard-of-care imaging, within 4 weeks of liver resection surgery, within 12 months of orthotopic liver transplant and prior to therapy ]
    The Standardized Uptake Value (SUV) for 18F-FDG PET images will be determined in the hepatocellular carcinoma (HCC) tumor lesions and background liver (normal tissue). These metrics include SUVmax, SUVpeak, or SUVmean and are common PET imaging measures.
  • Pharmacokinetics of 18F-FSPG, 11C-acetate, and 18F-FDG [ Time Frame: Within 4 weeks of standard-of-care imaging, within 4 weeks of liver resection surgery, within 12 months of orthotopic liver transplant and prior to therapy ]
    The pharmacokinetics of 18F-FSPG, 11C-acetate and 18F-FDG uptake will be determined using compartmental modeling of PET imaging data. Venous samples will be collected over the course of 18F-FSPG, 11C-acetate and 18F-FDG scans to confirm blood pool radioactivity, evaluate metabolism, and to calibrate image-derived input functions. We will also utilize blood samples collected prior to scanning to assay plasma levels of carbon-12 acetate and glucose in each patient to explore normalizing pharmacokinetic parameters across patients.
  • Number of lesions [ Time Frame: Within 4 weeks of liver resection surgery, within 12 months of orthotopic liver transplant and prior to therapy ]
    The number of lesions detected by 18F-FSPG PET will be determined and compared to the number of lesions detected by standard-of-care MRI, 11C-acetate PET, or 18F-FDG PET on a per patient basis.
  • Sensitivity of 18F-FSPG PET imaging [ Time Frame: Within 4 weeks of standard-of-care imaging, within 4 weeks of liver resection surgery, within 12 months of orthotopic liver transplant and prior to therapy ]
    Sensitivity is defined as the true positive rate. It is defined as true positive/(true positive + false negative). The determination of HCC status will be based on diagnostic pathology.
  • Specificity of 18F-FSPG PET imaging [ Time Frame: Within 4 weeks of standard-of-care imaging, within 4 weeks of liver resection surgery, within 12 months of orthotopic liver transplant and prior to therapy ]
    Specificity is defined as the true negative rate. It is defined as true negative/(true negative + false positive). The determination of HCC status will be based on diagnostic pathology.
  • Diagnostic pathology [ Time Frame: After surgery; Through study completion, up to 4 years ]
    Tissue samples will be obtained for patients following either liver resection surgery or orthotopic liver transplant. Pathology will be performed on these tumor tissues as the gold-standard assessment to confirm the presence of HCC tumor. Histology will be correlated to PET imaging data.
  • Tumor grade [ Time Frame: After surgery; Through study completion, up to 4 years ]
    Tissue samples will be obtained for patients following either liver resection surgery or orthotopic liver transplant. Tumor grade will be determined from pathology of tissue samples and correlated to PET imaging data for 18F-FSPG, 11C-acetate and 18F-FDG PET. The concordance of 18F-FSPG PET/CT and 11C-acetate PET/CT or 18F-FSPG PET/CT and 18F-FDG PET/CT will be evaluated. This will determine whether 18F-FSPG can be used singularly in place of combined use of 11C-acetate PET/CT (which typically detects low grade HCC) and 18F-FDG PET/CT (which typically detects high grade HCC).
  • Immunohistochemistry [ Time Frame: After surgery; Through study completion, up to 4 years ]
    Tissue samples will be obtained for patients following liver resection surgery. The expression of immunohistochemical markers (ie. xC- and CD44) will be evaluated in these tumor tissues on an ordinal scale of 0, 1, 2 or 3 and correlated to 18F-FSPG PET imaging data. In addition, markers of inflammation and immune cell recruitment (ie. CD86, CD163, CD3), proliferation (Ki67), and apoptosis (Caspase 3) will also be evaluated and correlated to 18F-FSPG PET imaging data.
Original Primary Outcome Measures  ICMJE
 (submitted: February 26, 2015)
Change in lesion 18F-FSPG PET standardized uptake value (SUV) compared to background (normal liver tissue) [ Time Frame: Within 4 weeks of surgery ]
A two-sided type I error rate of 5%, using a paired t-test will be used to test that lesion 18F-FSPG PET SUV's are significantly greater than background (normal liver tissue). Diagnostic pathology and immunoreactivity (xC-, cluster of differentiation 44) from fresh liver resection specimens, and OLT when possible, will be carried out. SUV will be summarized using the mean and standard deviation as well as a five number summary including the 25th, 50th, and 75th percentiles and the minimum and maximum values.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: January 24, 2020)
  • Metabolic profile [ Time Frame: After surgery; Through study completion, up to 4 years ]
    HCC tumor and non-cancerous liver tissue samples will be obtained for patients following liver resection surgery. Overall, tumoral tissue, peritumoral tissue and grossly normal surrounding liver will be evaluated. Metabolic profiles will be analyzed by mass spectrometry. The unbiased metabolomic phenome will be determined and correlated to 18F-FSPG PET.
  • Milan classification [ Time Frame: Baseline prior to imaging and surgery ]
    Milan criteria will be applied to standard-of-care (SOC) MRI images. The number and size of lesions will be determined. A patient will be deemed to meet Milan criteria if they exhibit A) A single lesion 2 to 5 cm in diameter or B) Three or fewer tumors, each measuring 1 to 3 cm in diameter, and C) No evidence of extrahepatic involvement or microvascular invasion. The proportion of patients whose Milan classification by novel imaging classification changed following validation by histological confirmation will be determined.
Original Secondary Outcome Measures  ICMJE
 (submitted: February 26, 2015)
  • Difference in number of lesions detected between imaging modalities (18F-FSPG PET, 11C-acetate PET) [ Time Frame: Within 4 weeks of surgery ]
    The paired t-test will be used to compare lesion counts. Continuous variables will be summarized using the mean and standard deviation as well as a five number summary including the 25th, 50th, and 75th percentiles and the minimum and maximum values.
  • Detection of poorly differentiated HCC lesions with 18F-FSPG PET missed by 11C-acetate PET [ Time Frame: Within 4 weeks of surgery ]
    Continuous variables will be summarized using the mean and standard deviation as well as a five number summary including the 25th, 50th, and 75th percentiles and the minimum and maximum values. The paired t-test will be used to compare lesion counts.
  • Correlation of PET imaging data (SUV) with ordinal immunohistochemical (IHC) scoring (0-3) of ex vivo liver tissue [ Time Frame: Within 4 weeks of surgery ]
    All imaging data (SUV) will be correlated to definitive, ex vivo diagnostic pathology and immunoreactivity (xC-, CD44), which will be carried out for every liver resection patient, and, when feasible, for every OLT patient. IHC scoring will be in terms of perceived strength of staining (scored on an ordinal scale of 0-3). However, such correlations may not be possible with many of the OLT patients, given the highly variable timeframe from transplant eligibility to actual surgery.
  • Proportion of patients whose Milan classification by novel imaging classification changed following validation by histological confirmation [ Time Frame: Within 4 weeks of surgery ]
    The chi-square test will be used to compare categorical outcomes among independent groups (patient level sensitivity by imaging modality, HCC differentiation classification).
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures
 (submitted: February 26, 2015)
18F-FSPG PET sensitivity and specificity as a function of standard uptake value (SUV) and definitive pathology. [ Time Frame: Within 4 weeks of surgery ]
The correlation of multiple lesions within the same liver will be accounted for with models of sensitivity (every tumor detected) and specificity (only tumor detected); specifically, we are characterizing the ability of PET imaging (SUV) to detect tumors as compared to IHC (ordinal scoring) results. This treatment of lesion-based sensitivity and specificity has not been described in the HCC literature. Consequently, the analysis approach will be generalized by using generalized linear models (using generalized estimating equations (GEE) for clustered (lesions within the same liver) as appropriate) for proportions (binomial), counts (Poisson), and continuous (Gaussian) variables, assuming logit, log, and identity links. Standard goodness-of-fit and residual analyses will be conducted.
 
Descriptive Information
Brief Title  ICMJE 18F-FSPG PET in Imaging Patients With Liver Cancer Before Undergoing Surgery or Transplant
Official Title  ICMJE PET Imaging of Hepatocellular Carcinoma With 18F-FSPG
Brief Summary This clinical trial studies fluorine F 18 L-glutamate derivative BAY94-9392 (18F-FSPG) positron emission tomography (PET) in imaging patients with liver cancer before undergoing surgery or transplant. Diagnostic procedures, such as 18F-FSPG PET, may help find and diagnose liver cancer and find out how far the disease has spread.
Detailed Description

PRIMARY OBJECTIVES:

I. To evaluate the relationship between 18F-FSPG PET/computed tomography (CT), pathology, and cancer metabolism in patients with suspected hepatocellular carcinoma (HCC) scheduled for liver resection surgery and orthotopic liver transplant (OLT).

II. To compare 18F-FSPG PET/CT with standard-of-care (SOC) diagnostic MRI imaging in patients with suspected HCC scheduled for liver resection surgery or OLT.

III. To compare the uptake of 18F-FSPG PET/CT with 11C-acetate PET/CT AND 18F-FDG PET/CT in suspected HCC and background liver in patients scheduled for liver resection surgery or OLT.

IV. To evaluate uptake of 18F-FSPG PET/CT in benign liver lesions compared to background.

V. To evaluate uptake of 18F-FSPG PET/CT in malignant non-HCC liver tumors.

OUTLINE:

Patients undergo 18F-FSPG PET and either carbon-11 (11C)-acetate PET or 18F-FDG PET scans within 4 weeks of surgery or OLT.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:
Cohorts A and B are Parallel. Cohorts C and D are Single Group.
Masking: None (Open Label)
Primary Purpose: Diagnostic
Condition  ICMJE
  • Adult Hepatocellular Carcinoma
  • Resectable Hepatocellular Carcinoma
  • Cholangiocarcinoma
  • Benign Liver Tumor
  • Metastases to Liver
Intervention  ICMJE
  • Biological: Fluorine F 18 L-glutamate Derivative 18F-FSPG
    Undergo 18F-FSPG PET scan
    Other Name: BAY94-9392
  • Biological: Carbon C 11 Acetate
    Undergo 11C-acetate PET scan
    Other Name: 11C-acetate
  • Procedure: Positron Emission Tomography
    Undergo 18F-FSPG, 11C-acetate, or 18F-FDG PET
    Other Names:
    • Medical Imaging, Positron Emission Tomography
    • PET
    • PET Scan
    • Positron Emission Tomography Scan
  • Other: Laboratory Biomarker Analysis
    Correlative studies
  • Biological: Fluorine F 18 2-deoxy-2-(18F)fluoro-D-glucose
    Undergo 18F-FDG PET scan
    Other Name: 18F-FDG
Study Arms  ICMJE
  • Experimental: Diagnostic (18F-FSPG PET)
    Patients undergo an 18F-FSPG PET scan within 4 weeks of surgery or OLT. Patients may also receive a second 18F-FSPG PET scan following standard-of-care treatment.
    Interventions:
    • Biological: Fluorine F 18 L-glutamate Derivative 18F-FSPG
    • Procedure: Positron Emission Tomography
    • Other: Laboratory Biomarker Analysis
  • Experimental: Diagnostic (11C-Acetate PET or 18F-FDG PET)
    Patients may undergo either carbon-11 (11C)-Acetate PET or 18F-FDG PET scans within 4 weeks of surgery or OLT.
    Interventions:
    • Biological: Fluorine F 18 L-glutamate Derivative 18F-FSPG
    • Biological: Carbon C 11 Acetate
    • Procedure: Positron Emission Tomography
    • Other: Laboratory Biomarker Analysis
    • Biological: Fluorine F 18 2-deoxy-2-(18F)fluoro-D-glucose
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Not yet recruiting
Estimated Enrollment  ICMJE
 (submitted: July 7, 2021)
80
Original Estimated Enrollment  ICMJE
 (submitted: February 26, 2015)
50
Estimated Study Completion Date  ICMJE May 31, 2025
Estimated Primary Completion Date May 31, 2024   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Diagnosis of HCC with one or more of the following:

    1. Liver mass with non-rim arterial phase hyperenhancement (APHE) and one of the following:

      1. 10-19 mm with >= 2 additional major features according to LI-RADS criteria ("washout", enhancing "capsule", and/or threshold growth),
      2. 10-19 mm with "washout" and visibility at antecedent ultrasound (US) but with no "capsule" or threshold growth,
      3. 10-19 mm with >= 50% size increase in <= 6 months but with no "washout" or "capsule"

        or

      4. >= 20 mm with >= 1 additional major feature according to LI-RADS criteria ("washout", enhancing "capsule", or threshold growth).
    2. Suggestive imaging findings plus AFP > 200 mg/dL; or
    3. Tumor confirmed by arteriography. or
  2. Diagnosis of a benign liver tumor with the following characteristics:

    1. Liver mass (>= 1 cm) that has suggestive imaging findings of a benign liver mass (adenoma, hemangioma, focal nodular hyperplasia).
    2. Prior SOC MRI of the benign liver lesion within 4 weeks of enrollment

    or

  3. Diagnosis of a malignant non-HCC liver tumor with one or more of the following characteristics:

    1. Liver mass (>= 1 cm) that is biopsy proven metastatic disease (metastatic colorectal cancer, metastatic pancreatic cancer).
    2. Liver mass (>= 1 cm) that is a non-HCC primary malignancy (cholangiocarcinoma).
    3. Prior SOC MRI of the malignant non-HCC liver tumor within 4 weeks of enrollment

and

3. Each patient must have completed conventional imaging and staging and MRI before initiation of the investigational PET studies.

and

4. Patients with HCC or cholangiocarcinoma must be a candidate for liver resection or orthotopic liver transplant (OLT)

Exclusion Criteria:

  1. Patients under the age of 18 will be excluded from this study.
  2. Patients who have HCC or cholangiocarcinoma but are not candidates for liver resection surgery or OLT
  3. Patients with a known prior malignancy who have received systemic chemotherapy within five years. Basal cell carcinoma of the skin, carcinoma in situ of the cervix, prior HCC, and patients with liver mass(es) proven to be metastatic disease are not excluded.
  4. Pregnant and breastfeeding patients.
  5. Patients with poorly controlled diabetes mellitus (fasting blood glucose level > 200 mg/dL).
  6. Patients with a known Infiltrative variant of HCC.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Lesley Flynt, MD 713-745-8760 lflynt@mdanderson.org
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02379377
Other Study ID Numbers  ICMJE 2020-1084
NCI-2015-00184 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
U24CA220325 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party M.D. Anderson Cancer Center
Study Sponsor  ICMJE M.D. Anderson Cancer Center
Collaborators  ICMJE National Cancer Institute (NCI)
Investigators  ICMJE
Principal Investigator: Lesley Flynt, MD M.D. Anderson Cancer Center
PRS Account M.D. Anderson Cancer Center
Verification Date September 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP