(P 385) FIRST IN HUMAN PHASE I TRIAL OF A NOVEL DRUG DELIVERY IMPLANT MATRIX WITH SN-38 (CEB-01) FOR RETROPERITONEAL SOFT TISSUE SARCOMA

Objective: Local recurrence after radical surgery for retroperitoneal soft tissue sarcoma (RPS) occurs in 41–50% of patients in expert centres and constitutes a major cause of death. We assess the role of CEB-01, a biocompatible and biodegradable membrane implant with PLGA nanofibers entangled with SN-38 (7-ethyl-10-hydroxy-camptothecin), the active metabolite of irinotecan, for a steady delivery, when placed in the surgical bed after RPS resection, to increase local control rates and survival in patients with RPS.

Methods: This is a multicentre, open label, first in human trial (EudraCT: 2018-001026-25, NCT04619056) following a 3+3 dose escalation design, and an expansion cohort at the recommended phase II dose (RP2D) in up to 21 participants. Primary objective is RP2D. Safety, efficacy, time to recurrence (based on RECIST 1.1), biomarkers, pharmacokinetics (PK) are secondary objectives. Efficacy is evaluated using RECIST 1.1. CEB-01 is implanted in the retroperitoneum of the patient immediately after surgery and placed on all surfaces that were in contact with and/or were infiltrated by the tumour (if > 5 cm at staging), including any organs, such as the spleen and great vessels; membranes are fixed with titanium clips to allow for better follow-up of disease in imaging assessments during the trial. If complete resection cannot be performed, CEB-01 is placed to cover all unresected areas.

Results: At present, 11 participants have been enrolled: 4 female / 7 male; mean age 63.45 years (range 40 - 77). Specific histologies include dedifferentiated liposarcoma (LPS) (4 cases), well differentiated LPS (5), liposarcoma-myxoid: 1 and leiomyosarcoma (1). Seven patients had previously unresected primary lesions, and 4 were locoregional relapses. The tumors’ longest dimension ranged from 51 to 354 mm (median 152 mm). Grade was 1 in 3 cases, grade 2 in 3 cases, grade 3 in 1 case and unknown in 4 cases. Post-surgery margins were R0 in 8 cases, R1 in 2 cases and unknown in 1 case. CEB-01 was implanted in 3 dose-increasing cohorts: 1st) 2 membranes of 180 cm2 each, 25 mcg/cm2, totalling 9 mg; 2nd) 2 membranes of 180 cm2 each, 50 mcg/cm2, totalling 18 mg and 3rd) 4 membranes of 180 cm2 each, 50 mcg/cm2, totalling 36 mg. No dose limiting toxicity (DLT) has been observed in any of the 3 cohorts. The profile of the adverse events (AEs) is similar to those post-surgery of RPS. Death occurred in 3 patients, due to either abdominal infection or bleeding (both unrelated) or retroperitoneal haemorrhage (related).
The expansion phase is ongoing. With a median follow-up of 16.3 months (range, 2.1 to 24.9 months), 2 local recurrences in the implant area have been observed after 5.5- and 8.6-months post-surgery, both with the lower dose (9 mg). Two patients have completed 24 months of follow-up. In 5 ongoing patients no recurrences have been observed after 2.1 to 17.8 months of follow-up (median 16.2 months). PK of SN-38 shows a dose linearity, with a half-life ranging from 287 to 372 hours (29 hours when administered as irinotecan 320 mg/m2), Cmax: 0.76- 3.58 ng/ml (68 ng/ml as irinotecan 320 mg/m2) and AUC 0-t: 128- 377 ng/ml*h (474 ng/ml as irinotecan 320 mg/m2). Blood levels of SN-38 were detectable at least up to 28 days after surgery.

Conclusion: CEB-01 is safe, well-tolerated and no dose-limiting toxicity has been observed at either dosage level. Adverse events are similar to those observed post RPS surgery. Local recurrence in the area of the membrane has occurred in 2 out of 10 patients (both treated with the lower dose). No recurrence has been observed after a median follow-up of 16.2 months in the rest of the ongoing patients. CEB-01 provides a local steady and prolonged release of SN-38, with a much lower Cmax than when SN-38 is administered as irinotecan.