Interim analysis of feasibility, safety, and tumor control in two first-in-human trials of a novel alpha-emitting radionuclide for pancreatic adenocarcinoma.

741 Background: This study aims to report the initial feasibility, safety, and tumor response of delivering Diffusing Alpha-Emitter Radiation Therapy (Alpha DaRT) to the pancreas. This innovative approach involves the interstitial implantation of a novel alpha-emitting radiation source via endoscopic ultrasound (EUS) for the treatment of pancreatic cancer. Methods: The study enrolled patients treated with Alpha DaRT to the pancreas across two protocols (PANC and ALL). The primary objective was to assess the safety of Alpha DaRT delivery to the target lesion via EUS, while the secondary objective was to evaluate initial tumor response using the Response Evaluation Criteria in Solid Tumors version 1.1 at 1 and 3 months post-Alpha DaRT source insertion. Toxicity was evaluated according to the Common Terminology Criteria for Adverse Events version 4.03. The PANC protocol included patients with biopsy-proven adenocarcinoma, either unresectable, recurrent, or metastatic, who were unfit for standard treatment. The ALL protocol allowed for any malignancy with a targetable lesion and permitted concurrent systemic therapy. For this analysis, only patients from the ALL protocol with pancreatic adenocarcinoma treated to the primary tumor were included. Pre-procedure planning involved CT simulation and EUS, and EUS-guided Alpha DaRT placement was confirmed by CT. The median follow-up time was 91 days. Results: A total of 12 patients (9 male, 3 female) median age 73 (range: 59-85) were enrolled (4 in PANC, 8 in ALL). Four patients had localized, unresectable disease and eight had metastatic disease. Three patients had a history of prior radiotherapy. Successful placement of Alpha DaRT sources into the targetable pancreatic lesions was achieved in all cases (100%), as confirmed by post-treatment imaging. Grade 1-2 acute toxicities included fever in 2 of 12 patients (16.7%), fatigue/weakness in 2 of 12 patients (16.7%) and abdominal or back pain in 3 of 12 patients (25.0%). One patient was hospitalized for obstructive jaundice (Grade 3) possibly secondary to inflammation seven days post-implantation requiring percutaneous transhepatic cholangiography; all hepatic laboratory values returned back to normal post procedure. All adverse events resolved. No long-term toxicities ( > 3 months) have been seen to date. Tumor response data were available for 8 of 12 patients. Local control was 100% for all evaluable patients. Of these, 6 (75.0%) exhibited stable disease, while 2 (25.0%) showed a partial response ( > 30% tumor reduction). One patient had a complete metabolic response on PET-CT at both the primary pancreatic lesion and liver metastasis. Conclusions: Alpha DaRT delivered via endoscopy is feasible with a favorable safety profile and demonstrates promising tumor responses. Ongoing longer follow-up and larger studies are required to validate these findings. Clinical trial information: NCT05781555 and NCT05657743 .