Randomized phase II study of trabectedin in patients with liposarcoma and leiomyosarcoma (L-sarcomas) after failure of prior anthracylines (A) and ifosfamide (I)

Abstract

10060 Background: Trabectedin, a marine-derived antineoplastic agent, binds to the minor groove of DNA and has previously shown activity in L-sarcomas in single-arm trials. This multicenter, randomized study aimed to characterize the anticancer efficacy with two dosing regimens of trabectedin in pts with treatment-refractory L-sarcomas. Methods: Eligible pts had measurable advanced L-sarcoma, progression despite at least prior A and I, PS 0–1 and adequate organ function. Pts were randomized to IV trabectedin, 1.5 mg/m2, 24h every 3 weeks (q3wk-24h) or 0.58 mg/m2, 3h weekly × 3 on a 28-day cycle (qwk-3h). Primary endpoint is time-to-progression (TTP) and secondary endpoints PFS, overall survival, response, and safety. With 217 events, study provided 90% power to detect a 37% risk reduction in TTP (2-sided 5% significance). Results: 270 pts were randomized as of 5/31/06. Baseline characteristics were comparable: median (range) 2 (1–7) metastatic sites and 2 (1–6) prior regimens; 62% had additional prior agents; 67% had bulky (≥5cm) disease. In the q3wk-24h vs qwk-3h arms median n. cycles were 5 (1–37) vs 2 (1–21); 38% vs 19% received ≥7 cycles. In protocol-specified primary analysis, median (95% CI) TTP was 3.7 (2.1–5.4) vs 2.3 (2.0–3.5) mo [HR: 0.734; p=0.0302] favoring the q3wk-24h arm. Median PFS was 3.3 (2.1–4.6) vs 2.3 (2.0–3.4) mo [HR: 0.755; p=0.0418] and median survival (n=175 events) was 13.8 (12.5–17.9) vs. 11.8 (9.9–13.9) mo [HR: 0.823; p=0.1984]. Benefit from the q3wk-24h arm was more pronounced in pts with central pathology confirmed diagnosis of L-sarcomas. More neutropenia, ↑AST/ALT, emesis and fatigue occurred in the q3wk 24-h. Febrile neutropenia was rare (0.8–1.6%). No cumulative toxicities were noted. Conclusions: Trabectedin can provide clinical benefit to pts with L-sarcoma following failure of all conventional treatment options. Significantly better TTP was noted with the q3wk-24h regimen, although this resulted in somewhat more neutropenia and transaminitis without clinical consequences. No cumulative toxicities were apparent in either arm. Although both dosing regimens are efficacious, there appears to superior disease control with the q3wk-24h arm in this population. [Table: see text]