(P 225) TRABECTEDIN WITH CONCOMITANT RADIATION THERAPY FOR PATIENTS WITH RESECTABLE RETROPERITONEAL LIPOSARCOMA OR LEIOMYOSARCOMA: A PHASE I/II TRIAL OF SPANISH (GEIS), ITALIAN (ISG) AND FRENCH (FSG) GROUPS

Objective: Retroperitoneal sarcomas (RPS) accounts for approximately 10-15% of all soft tissue sarcomas (STS). Liposarcoma and leiomyosarcoma (L-sarcomas) are the most frequent subtypes and account for 85% of them. Trabectedin (T) is particularly active in L-sarcomas and preclinical data suggest that it has radiosensitizing properties. To date, the results from a phase I/II trial reported that T in combination with radiotherapy (RT) is feasible and show a favorable safety profile and antitumor activity both as pre-operative treatment in patients with resectable myxoid liposarcoma and those with progressing metastatic STS. We present here the data from the phase I part in patients with a centralized diagnosis of retroperitoneal and resectable L-sarcoma: G2-3 liposarcoma (if at least 30% is dedifferentiated) (DDLPS) and G2-3 leiomyosarcoma (LMS).

Methods: Patients with resectable high-grade L-sarcoma received 3 cycles of T in combination with RT (45 Gy) in 25 fractions (1.8 Gy/fraction) in neoadjuvant setting. The phase I has the classic 3+3 design. T was given at 1.5 mg/m2 (dose level 0) or at a de-escalated dose of 1.3 mg/m2 (dose level -1) as a 24-hour IV infusion with a portable pump, once every 3 weeks. Dose-limiting toxicity (DLT) was defined as grade ≥3 events excluding grade 3/4 neutropenia lasting < 5 days, grade 3 transaminitis without delayed T administration and grade 3/4 nausea/vomiting due to inadequate prophylaxis. Primary endpoint of phase I part was to evaluate the safety and tolerability of the combination and to determine the recommended dose for phase II part of the study.

Results: From February 2019 to May 2020, six adult (≥18 years) patients (M/F: 2/4) with median age 65 years (range: 22-76) and a median tumor size of 19 cm (range: 11-22.5) were enrolled. Four and one patients had grade 2 and 3 DDLPS respectively, and one patient had grade 2 LMS.

All patients received the planned 3 preoperative T cycles at 1.5 mg/m2 (dose level 0) and completed RT. The major grade 3/4 toxicities were neutropenia (3), leucopenia (2), anemia (1), nausea (1) and ALT elevation (1). There was one DLT: febrile neutropenia (> 5 days) and no treatment-related deaths.

No progression was observed during preoperative treatment. Based on central radiological review, 6 patients had stable disease by RECIST 1.1 criteria and of the 3 patients evaluable by CHOI, 2 had partial response.

All 6 patients underwent macroscopic complete resection of residual tumor at a median of 0.9 months (0.2-1.8) after the end of preoperative treatment. With a median follow-up of 36 months (range: 26-40), 1 patient developed lung metastases (G2 DDLPS) and 1 patient developed liver metastases plus local relapse (G3 DDLPS) at 5 and 2 months from surgery. Two patients died: one due to disease progression (G3 DDLPS) and one, without relapse, due to an infectious complication related to surgical treatment.

Conclusion: Trabectedin concurrent with radiotherapy administered preoperatively is feasible and well tolerated in resectable retroperitoneal L-sarcomas. Trabectedin at 1.5 mg/m2 is the recommended dose for phase II part. Clinical trial information: NCT02275286.