First experience with ²²⁴Radium-labelled microparticles (radspherin) after CRS-HIPEC for peritoneal metastasis in colorectal cancer (a phase 1 study).

3599 Background: Peritoneal metastasis (PM) from colorectal cancer carries a dismal prognosis. Improved survival can be achieved by combining extensive cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC). However, median time to recurrence is short (11-12 months) and there is a need for novel therapies to prevent subsequent PM. Radspherin consists of the α-emitting radionuclide radium-224 (224Ra), half-life 3.6 days, adsorbed to a suspension of biodegradable calcium carbonate microparticles, designed to give short-range radiation to the serosal peritoneal surface, aiming to kill remaining free cancer cells and small tumor cell clusters. Methods: A first-in-man phase 1 study (EudraCT 2018-002803-33) was conducted at two specialized CRS-HIPEC centers. Radspherin was injected in the abdominal cavity through a catheter 2 days after CRS-HIPEC. Dose escalation at increasing dose levels of 1-2-4-7-MBq, repeated injection and expansion cohorts evaluated the safety and tolerability of Radspherin, explored maximal tolerated dose and biodistribution by using single photon-emission computed tomography/computed tomography (SPECT/CT) imaging. Results from the planned safety interim analysis after completion of the dose-limiting toxicity (DLT) period are presented. Results: Twenty-three patients were enrolled, dose escalation cohort (14), repeated cohort (3) and expansion cohort (6). Nineteen patients were treated in Oslo/ 4 in Uppsala. Twelve patients had synchronous PM Stage IV and 11 metachronous PM (Stage II (6), Stage III (5). Disease-free interval 15 months (3-39); males (7), females (16); median age 64 years (28-78). Peritoneal cancer index was median 7 (3-19), operation time 395 minutes (194-515) and hospital stay 12 days (7-37). Accordion ≥3 grade events (6); including anastomotic leaks (2); abscess (1); drains (2) and missed lesion (1), all reported as serious adverse events (SAEs). The 7MBq dose was selected as recommended dose as no DLT was observed. A total of 185 treatment emergent adverse effects (TEAE) were recorded, most were of low grade and considered related to CRS and/or HIPEC. Few patients (7) had TEAEs considered related to a combined impact of Radspherin and CRS-HIPEC. The biodistribution of Radspherin showed a relatively even peritoneal distribution, and no patients had compartments of the abdominal cavity without radioactivity (cold spots), and low number had hot spots. Long-term safety, dosimetry and first efficacy results of Radspherin will be reported after 12 months follow up period. Conclusions: All dose levels of Radspherin were well tolerated with DLT not reached. No deaths occurred and no SAEs were considered related to Radspherin. The biodistribution of Radspherin showed good peritoneal distribution of the radiolabeled microparticles. Clinical trial information: 2018-002803-33.