Tailoring HIPEC with Patient-Derived Organoids in Colorectal Peritoneal Metastases: Results from the First Stage of the Prospective Phase II OrganoHIPEC Clinical Trial (Clinicaltrials.gov NCT06057298).

Background/Objectives: OrganoHIPEC is a phase-II, two-stage, open-label clinical trial that investigates if cytoreductive surgery (CRS) and patient-tailored HIPEC, based on a preclinical platform using patient-derived organoids, can improve disease control in peritoneal metastases from colorectal cancer (CRC-PM). Methods: Adults with limited CRC-PM and no distant metastases were included. CRC-PM were sampled for organoid development during diagnostic laparoscopy. These organoids were used in an in vitro HIPEC model to test various drugs suitable for intraperitoneal administration. After 3-6 months of systemic chemotherapy, patients without progression underwent CRS/HIPEC with personalized regimens based on organoid drug response. To detect an increase in 12-month peritoneal disease-free survival from 40% to 60%, 24 patients are needed. According to the two-stage design, if <7 of 10 patients in Stage-1 remain PM-free at 12 months, the trial is terminated. Results: Forty-seven patients were enrolled. Among 31 patients with available organoid data, the most active drugs were mitomycin-C (n = 14), cisplatin/mitomycin-C (n = 12), and low-dose (120 min) oxaliplatin (n = 4). No patient was sensitive to high-dose oxaliplatin (30 min) and cisplatin/doxorubicin. Ten patients had a potential follow-up >12 months. Peritoneal relapse occurred at 8 months in two patients, and one died of liver metastases at 7 months. Seven patients remained PM-free for >12 months (median 16.4, range 12.6-28.4). Conclusions: A comprehensive precision approach using patient-derived organoids to guide personalized HIPEC is feasible and shows promising early results. High-dose oxaliplatin is poorly active. As 7/10 patients achieved the endpoint of 12-month PM-free survival, Stage-1 was successfully completed. The trial is proceeding to Stage-2.