(P 341) A PHASE 1B STUDY TO EVALUATE PREOPERATIVE ERIBULIN IN COMBINATION WITH RADIATION IN RETROPERITONEAL SARCOMA

Objective: Management of retroperitoneal liposarcoma (RPLPS) is challenging due to large tumor sizes and complex anatomy. Recurrence rates remain high despite aggressive surgical resections. Preoperative radiation has been evaluated in clinical trials, however its role is not fully established yet. Eribulin is an FDA-approved cytotoxic microtubule inhibitor for the treatment of advanced liposarcoma. The aim of this study was to assess the safety and tolerability of preoperative eribulin in combination with radiation in patients with RPLPS.

Methods: In this open-label, phase 1B, dose-finding study, patients with primary or recurrent resectable retroperitoneal liposarcoma received escalating doses of eribulin and intensity-modulated radiation therapy (IMRT), guided by a modified toxicity probability interval (mTPI) design. Eribulin was administered on day 1 and 8, every 3 weeks for up to 3 cycles. Concurrent radiation began during cycle 1, following day 8 eribulin. The starting dose level of eribulin was 1.1 mg/m2, with dose level +1 escalation dose of 1.4 mg/m2, and the starting dose of IMRT was 50.4 Gy, with dose level –1 de-escalation dose of 39.6 Gy. Surgical resection occurred within 3-10 weeks after completion of radiation therapy. The primary endpoint was to determine the recommended phase 2 dose (RP2D) of concurrent eribulin and radiation. Secondary endpoints included rate of R0 resection, pathologic response, objective response rate (ORR), recurrence free survival (RFS), and overall survival (OS) rates. For exploratory objectives, patients underwent dynamic contrast-enhanced MRI (DCE-MRI) at three different time points during the preoperative period to evaluate for changes in tumor perfusion/permeability and microenvironment during and after chemoradiation. In addition, blood for ctDNA analysis was collected and patient-reported questionnaires (PROMIS) were completed at multiple time-points before and after surgery.

Results: Between June 2018 and January 2023, fifteen patients with resectable retroperitoneal liposarcoma were enrolled in the study. Seven patients were female (46.7%), with ages between 44 and 79 years (median age 62). Both well-differentiated (40%) and de-differentiated (60%) liposarcoma subtypes were enrolled. Thirteen patients were evaluable for dose-determining. Four patients treated at starting dose level had no dose-limiting toxicities (DLTs). Two out of the nine patients treated at dose level 2 had DLTs. One DLT was early resection due to disease progression, and the other one was sudden cardiac death, which was ultimately attributed to cardiac anomaly. There was one related serious adverse event (SAE) of febrile neutropenia. The RP2D was established at eribulin 1.4 mg/m2 and IMRT 50.4 Gy over 28 fractions. Twelve patients underwent surgery after completing preoperative study treatment, with six R0 (50%) and six R1 (50%) resections. The median RFS was 30.4 months (95% CI 12.0-NR), while the 2- and 5-year RFS rates were 71.6% (95% CI 33.7-90.3%) and 47.8% (95% CI 15.3-74.8%) respectively. DCE-MRI, ctDNA and PROMIS data are currently under analysis and will be presented.

Conclusion: A preoperative chemoradiation protocol of eribulin in combination with IMRT showed a manageable safety profile and warrants additional prospective evaluation for treatment of retroperitoneal liposarcoma. (This investigator-initiated trial was supported by Eisai Inc.; ClinicalTrials.gov number, NCT03361436.)