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First experience with (224)Radium-labeled microparticles (Radspherin®) after CRS-HIPEC for peritoneal metastasis in colorectal cancer (a phase 1 study)
BACKGROUND: Peritoneal 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 t...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10016379/ https://www.ncbi.nlm.nih.gov/pubmed/36936230 http://dx.doi.org/10.3389/fmed.2023.1070362 |
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author | Larsen, Stein Gunnar Graf, Wilhelm Mariathasan, Anthony Burton Sørensen, Olaf Spasojevic, Milan Goscinski, Mariusz Adam Selboe, Silje Lundstrøm, Nadja Holtermann, Anne Revheim, Mona-Elisabeth Bruland, Øyvind Sverre |
author_facet | Larsen, Stein Gunnar Graf, Wilhelm Mariathasan, Anthony Burton Sørensen, Olaf Spasojevic, Milan Goscinski, Mariusz Adam Selboe, Silje Lundstrøm, Nadja Holtermann, Anne Revheim, Mona-Elisabeth Bruland, Øyvind Sverre |
author_sort | Larsen, Stein Gunnar |
collection | PubMed |
description | BACKGROUND: Peritoneal 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 ((224)Ra), 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. METHODS: A 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. RESULTS: Twenty-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. CONCLUSION: All 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. |
format | Online Article Text |
id | pubmed-10016379 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-100163792023-03-16 First experience with (224)Radium-labeled microparticles (Radspherin®) after CRS-HIPEC for peritoneal metastasis in colorectal cancer (a phase 1 study) Larsen, Stein Gunnar Graf, Wilhelm Mariathasan, Anthony Burton Sørensen, Olaf Spasojevic, Milan Goscinski, Mariusz Adam Selboe, Silje Lundstrøm, Nadja Holtermann, Anne Revheim, Mona-Elisabeth Bruland, Øyvind Sverre Front Med (Lausanne) Medicine BACKGROUND: Peritoneal 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 ((224)Ra), 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. METHODS: A 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. RESULTS: Twenty-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. CONCLUSION: All 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. Frontiers Media S.A. 2023-03-01 /pmc/articles/PMC10016379/ /pubmed/36936230 http://dx.doi.org/10.3389/fmed.2023.1070362 Text en Copyright © 2023 Larsen, Graf, Mariathasan, Sørensen, Spasojevic, Goscinski, Selboe, Lundstrøm, Holtermann, Revheim and Bruland. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Medicine Larsen, Stein Gunnar Graf, Wilhelm Mariathasan, Anthony Burton Sørensen, Olaf Spasojevic, Milan Goscinski, Mariusz Adam Selboe, Silje Lundstrøm, Nadja Holtermann, Anne Revheim, Mona-Elisabeth Bruland, Øyvind Sverre First experience with (224)Radium-labeled microparticles (Radspherin®) after CRS-HIPEC for peritoneal metastasis in colorectal cancer (a phase 1 study) |
title | First experience with (224)Radium-labeled microparticles (Radspherin®) after CRS-HIPEC for peritoneal metastasis in colorectal cancer (a phase 1 study) |
title_full | First experience with (224)Radium-labeled microparticles (Radspherin®) after CRS-HIPEC for peritoneal metastasis in colorectal cancer (a phase 1 study) |
title_fullStr | First experience with (224)Radium-labeled microparticles (Radspherin®) after CRS-HIPEC for peritoneal metastasis in colorectal cancer (a phase 1 study) |
title_full_unstemmed | First experience with (224)Radium-labeled microparticles (Radspherin®) after CRS-HIPEC for peritoneal metastasis in colorectal cancer (a phase 1 study) |
title_short | First experience with (224)Radium-labeled microparticles (Radspherin®) after CRS-HIPEC for peritoneal metastasis in colorectal cancer (a phase 1 study) |
title_sort | first experience with (224)radium-labeled microparticles (radspherin®) after crs-hipec for peritoneal metastasis in colorectal cancer (a phase 1 study) |
topic | Medicine |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10016379/ https://www.ncbi.nlm.nih.gov/pubmed/36936230 http://dx.doi.org/10.3389/fmed.2023.1070362 |
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