First-in-human CEB-01: Novel loco-regional SN-38 release membrane to prevent local recurrence in retroperitoneal sarcomas.
Authors: González-Lopez José Antonio , Sebio Ana , Hindi Nadia , Jimenez Montiel , Villarejo-Campos Pedro , Martin-Broto Javier , Díaz-Beveridge Robert , Orbis Castellanos Juan Francisco , López Andújar Rafael , Álvarez Álvarez Rosa , Asencio José Manuel , Serrano Cesar , Rodríguez Conde Nivardo , Castro Boix Sandra , Krauel Gimenez-Salinas Lucas , Tornero García José Antonio , Perez Campos Antonio , Lopera Ester , Bertran Joan , López Pousa Antonio 
Published: June 2024

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Background: Local recurrence after radical surgery (SX) for retroperitoneal soft tissue sarcoma (RPS) occurs in up to 50% of patients and constitutes a major cause of death. CEB-01 is a novel biocompatible and biodegradable membrane implant of poly lactic-co-glycolic acid (PLGA) nanofibers entangled with SN-38 for a steady delivery in the surgical bed after RPS resection. CEB-01 may increase local control rates and survival. Methods: This is a multicentre, first in human trial (NCT04619056/EudraCT: 201800102625) following a 3+3 dose escalation design, and an expansion cohort. CEB-01 is implanted after SX at 3 dose levels of SN-38: 9 mg (2 membranes of 180 cm2 at 25 mcg/cm2), 18 mg, and 36 mg (4 membranes at 25 mcg/cm2 and 50 mcg/cm2, respectively). The primary objective was to determine the recommended phase 2 dose (RP2D) level, defined as <33% of patients experiencing dose limiting toxicity (DLT) within 2 weeks after SX. DLT is defined as any Grade ≥3 toxicity. Secondary endpoints included: efficacy by means of time to local relapse (TTLR), progression-free survival (PFS) evaluated using RECIST 1.1, and overall survival (OS); safety; pharmacokinetics (PK) and quality of life. The study included tumor central pathological review and independent data monitoring committee (IDMC) for efficacy and safety. Here we report the final results for the primary endpoint. Results: From Jul 2020 to Nov 2023, 14 patients were included: 10 male; mean age 63 years (range: 39 - 77), 8 with dedifferentiated liposarcoma (LPS), 4 well differentiated LPS, 1 myxoid LPS, and 1 leiomyosarcoma. Post-SX margins were R0 in 82% patients, and R1 in 18%. No dose limiting toxicity (DLT) was observed. RP2D was declared at 18 mg. With a median follow-up of 9.1 months (range: 1-21), no recurrence in the area of the membrane was reported at RP2D and only one patient presented a local recurrence distal to the membrane at 8.5 months after SX. All patients at RP2D were free of distal progressions and alive, with two patients having an OS > 20 months. Adverse events were similar to those post-SX. Grade 3 toxicities reported consisted of 1 patient who experienced retroperitoneal hemorrhage, 1 small intestine obstruction, 1 anemia and 1 fever. Three patients died due to disease progression at the dose level 1; and two at dose level 3, one due to cardiac arrest with bleeding (unrelated to CEB-01), and one due to retroperitoneal hemorrhage (related). SN-38’s PK showed dose linearity. At RP2D, the median half-life was 296 hours , Cmax: 0.75 ng/ml and AUC 0-t: 109 ng/ml*h. Blood levels of SN-38 were detectable 28 days after surgery. Conclusions: CEB-01 recommended phase II level is 18 mg. CEB-01 at 18 mg provides promising local disease control and a local steady and prolonged release of SN-38, with a much lower Cmax than irinotecan. An international phase 2 trial with CEB-01 at 18 mg to demonstrate local control is underway. Clinical trial information: NCT04619056 .