Functional Imaging of Liver Cancer (FLIC): Study protocol of a phase 2 trial of 18F-DCFPyL PET/CT imaging for patients with hepatocellular carcinoma

Abstract

Background: While prostate specific membrane antigen (PSMA) is overexpressed in high-grade prostate cancers, it is also expressed in tumor neovasculature and other malignancies, including hepatocellular carcinoma (HCC). Importantly, no functional imaging for HCC is clinically available, making diagnosis and surveillance following local therapies particularly challenging. 18F-DCFPyL binds with high affinity to PSMA yet clears rapidly from the blood pool. PET imaging with 18F-DCFPyL may represent a new tool for staging, surveillance and assessment of treatment response in HCC. The purpose of this Functional Imaging Liver Cancer (FLIC) trial is to assess the ability of 18F-DCFPyL-PET/CT to detect sites of HCC.

Methods: This is a phase II multi-site prospective imaging trial with a plan to enroll 50 subjects with suspected HCC on standard of care CT or MRI and eligible for standard local treatment. Participants will undergo a baseline 18F-DCFPyL-PET/CT, prior to therapy. Subjects will also be scanned with 18F-FDG-PET/CT within 2 weeks of 18F-DCFPyL-PET/CT. Participants will undergo histopathologic assessment and standard of care local treatment for HCC within a multidisciplinary team context. Participants with histopathologic confirmation of HCC and a positive baseline 18F-DCFPyL-PET/CT will undergo a post-treatment 18F-DCFPyL-PET/CT during the first routine follow-up, typically within 4-8 weeks. Subjects with negative baseline 18F-DCFPyL-PET/CT will not be re-scanned after treatment but will remain in follow-up. Participants will be followed for 5-years to assess for progression-free-survival. The primary endpoint is the positive predictive value of 18F-DCFPyL-PET for HCC as confirmed by histopathology. Secondary endpoints include comparison of 18F-DCFPyL-PET/CT with CT, MRI, and 18F-FDG-PET/CT, and evaluation of the value of 18F-DCFPyL-PET/CT in assessing treatment response following local treatment. Exploratory endpoints include next generation sequencing of tumors, and analysis of extracellular vesicles to identify biomarkers associated with response to therapy.

Discussion: This is a prospective imaging trial designed to evaluate whether PSMA-PET/CT imaging with 18F-DCFPyL can detect tumor sites, assess local treatment response in HCC patients, and to eventually determine whether PSMA-PET/CT could improve outcomes of patients with HCC receiving standard of care local therapy. Importantly, this trial may help determine whether PSMA-selective radiopharmaceutical therapies may be beneficial for patients with HCC.

Clinical trial registration: NIH IND#133631. Submission date: 04-07-2021. Safe-to-proceed letter issued by FDA: 05.07.2021. NIH IRB #00080. ClinicalTrials.gov Identifier NCT05009979. Date of Registry: 08-18-2021. Protocol version date: 01-07-2022.

Conflict of interest statement

The authors declare that they have no competing interests.

Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

Figures

Fig 1. Protocol schema.

Patients who have LIRADS 4 or 5 lesions on standard imaging (CT or MRI) and deemed good candidates for any local treatment are eligible for this study. Prior to treatment, PET/CT with both 18F-DCFPyL and 18F-FDG will be performed. Histopathologic confirmation of HCC will be performed on either biopsy or surgical specimen. Only patients who had positive 18F-DCFPyL PET/CT pre-treatment will undergo post-treatment 18F-DCFPyL PET/CT (2–3 months post treatment) to determine its utility as a functional imaging marker. Scale bar shown is 100 μm. The images were created with BioRender.com, with permission privileges.

Fig 2. Representative immunohistochemical staining for prostate-specific membrane antigen (PSMA) in formalin-fixed paraffin-embedded liver tissues.

PSMA expression was assessed using anti-PSMA antigen antibody (Cell Signaling, Danvers, MA; D718E clone) and avidin-biotin peroxidase immunohistochemistry. Hematoxylin and eosin staining of formalin-fixed paraffin-embedded human liver samples diagnosed as normal and hepatocellular carcinoma (HCC) are shown at the top of the image. High magnification images are shown in the inset. Scale bar shown is 100 μm. These images were created by co-author Joon-Yong Chung at the National Cancer Institute, with permission privileges for their use.

Fig 3. Study calendar.

Table numbers’ details: 1. Performed within 30 days prior to administration of 18F-DCFPyL unless otherwise indicated. Screening procedures such as medical assessment may be performed remotely via any NIH approved platforms. 2. Vital signs will be taken prior to injection of 18F-DCFPyL and following completion of the final PET/CT scan (+ 15 minutes). 3. Acute care panel: sodium, potassium, chloride, total CO2, creatinine, glucose, urea nitrogen, eGFR 4. For female participants of childbearing age (in the absence of prior hysterectomy). Pregnancy tests may be performed as clinically indicated prior to each scan. 5. CT (Chest/Abdomen/Pelvis) and/or MRI (Abdomen) will be performed within 2 months of each 18F-DCFPyL PET/CT. Imaging may be performed at certified outside facility and provided to study team. 6. Subjects will undergo 18F-DCFPyL injection and a dynamic PET/CT. Approximately 1 hour (+/- 10 minutes) post 18F-DCFPyL injection, a static PET/CT imaging performed. Refer to section 3.2.2 for additional information regarding the scanning procedure. 7. 18F-FDG PET/CT will be performed within approximately 2 weeks before or after each 18F-DCFPyL scan. Each PET/CT imaging must be approximately a day apart. The order obtained for 18F-DCFPyL PET/CT and 18F-FDG PET/CT does not matter. 8. Event monitoring will be done at the time of injection, and 1 hour post injection. All subjects will be contacted by phone at ~1–3 business days post-injection and will be asked non-leading questions regarding symptoms. At the investigator’s discretion, subjects with safety concerns noted during the post injection period may remain at the site or be asked to return to the site to undergo further safety assessments at the 1–3 business day follow-up time point. 9. Tumor markers include Alpha-fetoprotein, carcinoembryonic antigen, carbohydrate antigen 19.9 (CA19.9) and liver function tests (Alkaline Phosphatase, ALT, AST, Total Bilirubin, Direct Bilirubin). Refer to section 5.1 for more details. 10. Only participants with a positive baseline 18F-DCFPyL-PET/CT scan (i.e. with the presence of DCFPyL-avid tumor/s) and a biopsy confirming HCC diagnosis will undergo visit 2 for a second 18F-DCFPyL PET/CT (during routine treatment follow up, typically within 4–8 weeks). 11. Follow-up will be performed every 3 months after the last 18F-DCFPyL scan (or after therapy for participants with negative baseline 18F-DCFPyL PET/CT and biopsy confirming HCC) for 2 years, and yearly afterwards for an additional 3 years. 12. If tumor recurrence occurs during the follow-up period, an 18F-DCFPyL PET/CT, 18F-FDG PET/CT, CT/MRI and biopsy may be performed any time after recurrence at PI discretion. Biopsy would be performed concurrently with treatment if the latter is performed.