Background <p>Retroperitoneal sarcoma (RPS) resection remains challenging, with up to 50% of patients developing local recurrence and a 5-year survival rate of 50%. CEB-01, designed for local and controlled SN-38 delivery postresection, may increase local control and survival rates.</p> Materials and Methods <p>CEB-01 is a first-in-human, multicenter trial following a 3+3 dose escalation design and expansion cohort conducted in six centers in Spain. CEB-01 was implanted at three dose levels of SN-38: 9, 18, and 36 mg. The objectives were to establish the recommended phase 2 dose (RP2D) and evaluate its safety, efficacy, and pharmacokinetics.</p> Results <p>From July 2020 to November 2023, 14 patients were included: 10 males, with a median age of 63 years (range: 40–76), mostly with dedifferentiated (50%) and well-differentiated liposarcoma (35.7%), and R0 (79%) and R1 (21%) postsurgical margins. No dose-limiting toxicities were observed, and the RP2D was set at 18 mg. With a median follow-up of 9.1 months (range: 1–21), all patients at RP2D were recurrence-free and alive. Grade ≥ 3 adverse events were reported in just one patient treated with RP2D.</p> <p>The pharmacokinetic profile of SN-38 showed substantially lower C_max (20–70-fold) and longer elimination half-life times than those of intravenous irinotecan at clinically relevant doses. CEB-01 showed prolonged release of SN-38, which was detectable after 28 days in circulating blood.</p> Conclusions <p>CEB-01 at 18 mg exhibited a tolerable safety profile and preliminary efficacy against postsurgery recurrence in patients with RPS. These results warrant further clinical investigations of this type of tumor.</p> <p><i>Clinical trial identification</i>: EU&#xa0;CT: 2024-516971-34-00; clinicaltrials.gov: NCT04619056.</p>