First experience with 224Radium-labeled microparticles (Radspherin®) after CRS-HIPEC for peritoneal metastasis in colorectal cancer (a phase 1 study)

Frontiers in Medicine

Medicine

Anthony Burton Mariathasan¹  Milan Spasojevic¹  Anne Holtermann¹  Olaf Sørensen¹  Mariusz Adam Goscinski¹  Stein Gunnar Larsen¹  Wilhelm Graf²  Silje Selboe³  Mona-Elisabeth Revheim⁴  Øyvind Sverre Bruland⁵  Nadja Lundstrøm⁶ 

[1] Department of Gastroenterological Surgery, Section for Surgical Oncology, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway;Department of Surgical Sciences, Uppsala University, Uppsala, Sweden;Uppsala Academic Hospital, Uppsala, Sweden;Division of Radiology and Nuclear Medicine, Oslo University Hospital, Oslo, Norway;Division of Radiology and Nuclear Medicine, Oslo University Hospital, Oslo, Norway;Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway;Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway;Department of Oncology, Oslo University Hospital, Oslo, Norway;Oncoinvent AS, Oslo, Norway;Uppsala Academic Hospital, Uppsala, Sweden;Department of Nuclear Medicine, Uppsala, Sweden;

关键词: metastatic colorectal cancer;    peritoneal metastasis;    cytoreductive surgery;    hyperthermic intraperitoneal chemotherapy;    Ra;    alpha emitter;    targeted alpha particle therapy;   

DOI  :  10.3389/fmed.2023.1070362

 received in 2022-10-14, accepted in 2023-01-23,  发布年份 2023

来源: Frontiers

【 摘 要 】

BackgroundPeritoneal metastasis (PM) from colorectal cancer carries a dismal prognosis despite extensive cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC). With a median time to recurrence of 11–12 months, there is a need for novel therapies. Radspherin® consists of the α-emitting radionuclide radium-224 (224Ra), which has a half-life of 3.6 days and is adsorbed to a suspension of biodegradable calcium carbonate microparticles that are designed to give short-range radiation to the serosal peritoneal surface linings, killing free-floating and/or tumor cell clusters that remain after CRS-HIPEC.MethodsA first-in-human phase 1 study (EudraCT 2018–002803-33) was conducted at two specialized CRS-HIPEC centers. Radspherin® was administered intraperitoneally 2 days after CRS-HIPEC. Dose escalation at increasing activity dose levels of 1-2-4-7-MBq, a split-dose repeated injection, and expansion cohorts were used to evaluate the safety and tolerability of Radspherin®. The aim was to explore the recommended dose and biodistribution using gamma-camera imaging. The results from the planned safety interim analysis after the completion of the dose-limiting toxicity (DLT) period of 30 days are presented.ResultsTwenty-three patients were enrolled: 14 in the dose escalation cohort, three in the repeated cohort, and six in the expansion cohort. Of the 23 enrolled patients, seven were men and 16 were women with a median age of 64 years (28–78). Twelve patients had synchronous PM stage IV and 11 patients had metachronous PM [primary stage II; (6) and stage III; (5)], with a disease-free interval of 15 months (3–30). The peritoneal cancer index was median 7 (3–19), operation time was 395 min (194–515), and hospital stay was 12 days (7–37). A total of 68 grade 2 adverse events were reported for 17 patients during the first 30 days; most were considered related to CRS and/or HIPEC. Only six of the TEAEs were evaluated as related to Radspherin®. One TEAE, anastomotic leakage, was reported as grade 3. Accordion ≥3 grade events occurred in a total of four of the 23 patients: reoperation due to anastomotic leaks (two) and drained abscesses (two). No DLT was documented at the 7 MBq dose level that was then defined as the recommended dose. The biodistribution of Radspherin® showed a relatively even peritoneal distribution.ConclusionAll dose levels of Radspherin® were well tolerated, and DLT was not reached. No deaths occurred, and no serious adverse events were considered related to Radspherin®.Clinical Trial Registration: Clinicaltrials.gov, NCT 03732781.

【 授权许可】

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Copyright © 2023 Larsen, Graf, Mariathasan, Sørensen, Spasojevic, Goscinski, Selboe, Lundstrøm, Holtermann, Revheim and Bruland.