Trabectedin phase II clinical trials: Pooled analysis of safety in patients with solid tumors

Abstract

e13510 Background: Trabectedin is an originally marine-derived antineoplastic agent. Its unique antitumor properties, attributed to specific binding to the small groove of DNA, have been demonstrated activity against soft-tissue sarcoma (STS), ovarian, breast and prostate cancer. Trabectedin treatment has been authorized by EMEA for STS after failure of standard treatment and shows efficacy in relapsed ovarian cancer in a phase III study. This retrospective report on safety includes single-agent trabectedin phase II studies in patients (pts) with solid tumors. Methods: A total of 1,132 pts were treated with trabectedin in 19 international trials (Feb’99 - Apr’08). Three schedules were analyzed: 24-hour infusion every 3 weeks (wk) (570 pts), 3-h every 3 wk (258 pts), and 3-h for 3 out of 4 wk (304 pts). Safety analyses included pts who received at least part of 1 infusion. MedDRA and NCI-CTC v1.0/2.0 were used to code and grade treatment-emergent adverse events (AEs). Results: Median pt age was 54 years with ECOG 0–1 (>99%). Diagnosis included sarcoma (56%), ovary (26%) and breast (7%) cancer, for which 90% of pts had received chemotherapy, 37.5% radiotherapy, and 96.0% surgery. Trabectedin lasted for a median of 3 cy (9.4 wks) and 28% of pts received ≥ 6 cycles, with a median dose intensity of 0.4 (0.1–0.6) mg/m2/wk. The overall rate of discontinuations due to toxicity was 10.3%, similar between all three dose schedules. Most common trabectedin-related AEs (≥ 20% of pts) were nausea, fatigue and vomiting. Most common lab abnormalities were reversible myelosuppression, mainly neutropenia (37% grade3–4) though G-CSF was given to less than 10% of pts; and transient transaminase increases (grade3–4: ALT, 45%; AST, 30%). Of note, only 3.7% and 5.7% of pts had alopecia or mucositis/stomatitis, respectively. Fifteen drug-related deaths (1.3%) occurred. Conclusions: Single-agent trabectedin was reasonably well tolerated, with low rates of drug-related discontinuations and deaths. Sustained clinical benefit in the absence of relevant cumulative toxicities allows its administration to patients for prolonged periods of time. [Table: see text]