Ignite Creation Date:
2025-12-25 @ 4:25 AM
Ignite Modification Date:
2025-12-26 @ 3:29 AM
Study NCT ID:
NCT06852820
Status:
NOT_YET_RECRUITING
Last Update Posted:
2025-09-23
First Post:
2025-02-25
Is NOT Gene Therapy:
False
Has Adverse Events:
False
Brief Title:
68Ga-PSMA-11 PET-directed Radioligand Therapy in Metastatic Hepatocellular Carcinoma (HCC)
Sponsor:
Melissa Lumish
Organization:
Study Overview
Official Title:
A Pilot Study of 68Ga-PSMA-11 PET-directed Radioligand Therapy in Patients With Metastatic Hepatocellular Carcinoma (HCC)
Status:
NOT_YET_RECRUITING
Status Verified Date:
2025-09
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
The purpose of this study is to look at the effects (good and bad) of a drug called 177Lu-PSMA-617 (also known as the study drug) when given to participants who have prostate specific membrane antigen (PSMA) positive liver cancer.
Detailed Description:
Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide, with more than 900,000 newly diagnosed cases and approximately 830,000 deaths in 2020. Surgical resection and liver transplantation are potential curative options for patients with early-stage HCC. However, most patients present with metastatic and/or unresectable disease and systemic treatment is the only therapeutic option for these patients.
Although several ICI-based combination therapies have recently extended survival for many patients with HCC, biomarker-directed strategies are limited for this disease. Prostate Specific Membrane Antigen (PSMA) is a protein that is expressed in prostate cells and overexpressed in prostate cancer and is accepted as a valuable theragnostic (combined diagnostic and therapeutic) target in metastatic castration-resistant prostate cancer. 68Ga-PSMA-11 PET (PSMA PET) is now utilized to select patients with metastatic prostate cancer for PSMA-directed therapy with 177Lu-PSMA-617. PSMA is now known to be expressed in a variety of solid tumors, including HCC, specifically in the neovasculature associated with solid tumors. However, there is a lack of data exploring whether there is a role for PSMA-directed therapy in non-prostate solid tumors.
Investigator performed PSMA IHC on 148 HCCs from surgical resection or liver explant specimens from patients at the Mayo Clinic, and 90% of HCCs showed PSMA immunostaining localized to the tumor endothelium. More than 50% of HCCs showed 31-100% PSMA immunostaining by area. In several cases, the normal liver background did show faint canalicular staining, highlighting the need to distinguish between normal tissue and tumor-associated expression.
In a similar study using immunohistochemistry (IHC) to evaluate PSMA expression in HCC, 79.2% of tumors showed high levels of PSMA expression at any location, with the majority of this expression occurring in a neovascular staining pattern (89.9%). One patient underwent imaging with PSMA PET which demonstrated intense and heterogeneous PSMA uptake in the HCC tumor.
Several additional reports have demonstrated that PSMA expression in HCC can be detected noninvasively by PSMA PET.20,21 Our group at Mayo Clinic prospectively evaluated PSMA uptake using Ga-PSMA PET in patients with treatment-naïve HCC. In 31 patients, 39 lesions were identified. In this study, 64% had high PSMA uptake (grade 3 or 4) and 36% had low PSMA uptake (grade 1 or 2). It is expected that PSMA uptake will be much higher in patients with advanced HCC. PSMA PET has been compared with MRI for detection of HCC and had similar efficacy to MRI in a cohort of 19 patients. Similarly, a meta-analysis of 6 studies including 126 patients imaged with PET/CT or PET/MRI with PSMA-targeting radiopharmaceuticals in patients with newly diagnosed or recurrent HCC showed a detection rate of greater than 85%.These studies clearly suggest that targeting PSMA could be an attractive target in patients with advanced HCC.
The VISION study was a phase 3 trial investigating the efficacy and safety of 177Lu-PSMA-617 (Lu-177 vipivotide tetraxetan) with standard of care in patients with previously treated metastatic castration-resistant prostate cancer who were identified as PSMA PET-positive. Similarly, the phase III PSMAfore study of Lu-177 vipivotide tetraxetan demonstrated improvement in radiographic progression-free survival in patients with metastatic castration-resistant prostate cancer after prior treatment.
In HCC, a recent preclinical study demonstrated that radioligand therapy using \[177Lu\]Lu-PSMA-617 and \[177Lu\]Lu-EB-PSMA-617 effectively suppressed tumor growth and prolonged survival time in PSMA-positive HCC xenograft mice. However, this strategy has not been prospectively utilized in patients with HCC after first-line therapy. There is limited clinical data examining the role of PSMA radioligand therapy in HCC. One study included 2 patients with no other systemic therapy options available and demonstrated insufficient tumor radiation dosing by intratherapeutic SPECT/CT-based dosimetry after only a single cycle of therapy. This data is limited by the short treatment course of only 1 cycle, which was inadequate to induce a response, small sample size, and heavy pre-treatment.
Although the pattern of PSMA expression in HCC is distinct from that in prostate cancer, there is evidence from tyrosine kinase inhibitor (TKI) efficacy that targeting the neovasculature via inhibition of angiogenesis in the local tumor environment can limit tumor growth and improve survival.
Although several ICI-based combination therapies have recently extended survival for many patients with HCC, biomarker-directed strategies are limited for this disease. Prostate Specific Membrane Antigen (PSMA) is a protein that is expressed in prostate cells and overexpressed in prostate cancer and is accepted as a valuable theragnostic (combined diagnostic and therapeutic) target in metastatic castration-resistant prostate cancer. 68Ga-PSMA-11 PET (PSMA PET) is now utilized to select patients with metastatic prostate cancer for PSMA-directed therapy with 177Lu-PSMA-617. PSMA is now known to be expressed in a variety of solid tumors, including HCC, specifically in the neovasculature associated with solid tumors. However, there is a lack of data exploring whether there is a role for PSMA-directed therapy in non-prostate solid tumors.
Investigator performed PSMA IHC on 148 HCCs from surgical resection or liver explant specimens from patients at the Mayo Clinic, and 90% of HCCs showed PSMA immunostaining localized to the tumor endothelium. More than 50% of HCCs showed 31-100% PSMA immunostaining by area. In several cases, the normal liver background did show faint canalicular staining, highlighting the need to distinguish between normal tissue and tumor-associated expression.
In a similar study using immunohistochemistry (IHC) to evaluate PSMA expression in HCC, 79.2% of tumors showed high levels of PSMA expression at any location, with the majority of this expression occurring in a neovascular staining pattern (89.9%). One patient underwent imaging with PSMA PET which demonstrated intense and heterogeneous PSMA uptake in the HCC tumor.
Several additional reports have demonstrated that PSMA expression in HCC can be detected noninvasively by PSMA PET.20,21 Our group at Mayo Clinic prospectively evaluated PSMA uptake using Ga-PSMA PET in patients with treatment-naïve HCC. In 31 patients, 39 lesions were identified. In this study, 64% had high PSMA uptake (grade 3 or 4) and 36% had low PSMA uptake (grade 1 or 2). It is expected that PSMA uptake will be much higher in patients with advanced HCC. PSMA PET has been compared with MRI for detection of HCC and had similar efficacy to MRI in a cohort of 19 patients. Similarly, a meta-analysis of 6 studies including 126 patients imaged with PET/CT or PET/MRI with PSMA-targeting radiopharmaceuticals in patients with newly diagnosed or recurrent HCC showed a detection rate of greater than 85%.These studies clearly suggest that targeting PSMA could be an attractive target in patients with advanced HCC.
The VISION study was a phase 3 trial investigating the efficacy and safety of 177Lu-PSMA-617 (Lu-177 vipivotide tetraxetan) with standard of care in patients with previously treated metastatic castration-resistant prostate cancer who were identified as PSMA PET-positive. Similarly, the phase III PSMAfore study of Lu-177 vipivotide tetraxetan demonstrated improvement in radiographic progression-free survival in patients with metastatic castration-resistant prostate cancer after prior treatment.
In HCC, a recent preclinical study demonstrated that radioligand therapy using \[177Lu\]Lu-PSMA-617 and \[177Lu\]Lu-EB-PSMA-617 effectively suppressed tumor growth and prolonged survival time in PSMA-positive HCC xenograft mice. However, this strategy has not been prospectively utilized in patients with HCC after first-line therapy. There is limited clinical data examining the role of PSMA radioligand therapy in HCC. One study included 2 patients with no other systemic therapy options available and demonstrated insufficient tumor radiation dosing by intratherapeutic SPECT/CT-based dosimetry after only a single cycle of therapy. This data is limited by the short treatment course of only 1 cycle, which was inadequate to induce a response, small sample size, and heavy pre-treatment.
Although the pattern of PSMA expression in HCC is distinct from that in prostate cancer, there is evidence from tyrosine kinase inhibitor (TKI) efficacy that targeting the neovasculature via inhibition of angiogenesis in the local tumor environment can limit tumor growth and improve survival.
Study Oversight
Has Oversight DMC:
True
Is a FDA Regulated Drug?:
True
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
False
Is an FDA AA801 Violation?: