Evaluation of [68Ga]PSMA-HBED-CC and [99mTc]PSMA I&S in Imaging-Guided Detection of Lymph Node Metastases in Prostate Cancer Undergoing Radical Prostatectomy

The primary objective of this study is to enhance the detection of **lymph node invasion** (LNI) in patients with **prostate cancer** (PCa) who are undergoing **robot-assisted radical prostatectomy** (RARP) combined with an **extended pelvic lymph node dissection** (ePLND). This is achieved by evaluating the role of **[99mTc]PSMA I&S** in improving the identification of metastatic lymph nodes. The clinical relevance of this objective lies in its potential to improve surgical outcomes and reduce the risk of cancer recurrence by ensuring more accurate removal of cancerous lymph nodes.

The clinical trial involves **male patients** diagnosed with **prostate cancer** who are candidates for surgical treatment through robot-assisted radical prostatectomy. The study population is restricted to individuals aged between 18 and 80 years, with a preoperative risk of lymph nodal invasion greater than 5% as determined by the Briganti nomogram. Participants are required to be in general good health, capable of understanding, and willing to sign a written informed consent document. The trial does not include female subjects or vulnerable populations. The sponsor has not provided information regarding the total number of participants or specific lifestyle considerations such as diet or physical activity. The selection criteria ensure that only those with biopsy-proven prostate cancer and a planned extended pelvic lymph node dissection are included in the study.

The clinical trial is designed to evaluate the efficacy of imaging-guided surgery in enhancing the detection of lymph node metastases in patients with **prostate cancer** undergoing radical prostatectomy and extended pelvic lymph node dissection. This is a Phase 4, randomized, double-blind, controlled trial, with an estimated duration from May 2021 to December 2025. The trial involves the administration of two investigational products, **[68GA]PSMA-HBED-CC** and **[99mTc]PSMA I&S**, both delivered via intravenous injection. The primary objective is to improve the identification of lymph node invasion in patients undergoing robot-assisted radical prostatectomy with extended pelvic lymph node dissection, utilizing 99mTc-PSMA-I&S.

Participants will be required to attend several study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, biopsy-proven prostate cancer, and a lymph node invasion risk greater than 5% according to the Briganti nomogram. Following the screening, participants will undergo the investigational procedure and subsequent follow-up visits to monitor outcomes and any adverse events. The end-of-study visit will conclude the trial, where the primary endpoint, the rate of lymph node invasion observed at final pathology, will be assessed. The expected length of participant involvement is approximately one year, with conditions for early termination including withdrawal of consent or adverse events that compromise participant safety.

The clinical trial involves the administration of two experimental medications. The first medication is **[68GA]PSMA-HBED-CC**, which is provided in the form of an **injection/infusion**. This compound is a chemical substance with the active ingredient being 2-[[5-[3-[[6-[[(5S)-5-carboxy-5-[[(1S)-1,3-dicarboxypropyl]carbamoylamino]pentyl]amino]-6-oxohexyl]amino]-3-oxopropyl]-2-oxidophenyl]methyl-[2-[[5-(2-carboxyethyl)-2-oxidophenyl]methyl-(carboxylatomethyl)amino]ethyl]amino]acetate:gallium-68(3+) hydron. The medication is administered via **intravenous use**. The maximum daily dose is 160 MBq, with a total dose not exceeding 160 MBq over a treatment period of one day. Participant compliance is monitored to ensure adherence to the dosing schedule.

The second experimental medication is **[99mTc]PSMA I&S**, which is also administered as an **injection**. This substance is categorized as a protein of other origin, with the active ingredient being [99MTC]PSMA I&S. Similar to the first medication, it is administered through **intravenous use**. The maximum daily dose for this medication is 850 MBq, with a total dose not exceeding 850 MBq over a treatment period of one day. Compliance with the dosing regimen is closely monitored to ensure accurate administration.

Both medications are utilized in the context of a clinical trial aimed at improving the detection of lymph node metastases in prostate cancer patients undergoing radical prostatectomy and extended pelvic lymph node dissection. No non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, are specified in the trial protocol. The trial is conducted under the auspices of Ospedale San Raffaele, ensuring adherence to regulatory standards and ethical guidelines.

Efficacy in this clinical trial will be assessed by evaluating the primary endpoint, which is the rate of **lymph node involvement (LNI)** observed at final pathology following the use of 99mTc-PSMA-RGS. This assessment involves a histopathological evaluation of the lymph nodes, conducted by dedicated high-volume uropathologists. The results of this evaluation are typically available 10 days post-surgery. The trial aims to improve the detection of lymph node metastases in prostate cancer patients undergoing radical prostatectomy and extended pelvic lymph node dissection. The efficacy assessment will focus on the ability of 99mTc-PSMA-I&S to enhance the identification of LNI in this patient population.