Abstract
3074 Background: Trabectedin (Yondelis, ET-743) is a marine-derived compound, which binds to the minor groove of DNA and is active at nM concentrations. Trabectedin is thought to act through the transcription-coupled nucleotide excision repair system. In clinical studies trabectedin has demonstrated activity in soft tissue sarcoma, ovarian and breast cancer. Methods: Eligibility criteria included normal liver function tests, limited prior doxorubicin exposure (≤ 250 mg/m2), and normal cardiac function. PLD 30 mg/m2 was administered i.v. over one hour followed immediately by one of six trabectedin doses (0.4, 0.6, 0.75, 0.9, 1.1, and 1.3 mg/m2) i.v. over 3 hours every 21 days. The effect of the combination on the liver morphology was evaluated in biopsies obtained from consenting patients. Results: Six dose levels of trabectedin were evaluated. The DLTs were one grade 3 AST and two grade 4 ALT elevations observed at a trabectedin dose of 1.3 mg/m2. The recommended dose is trabectedin 1.1 mg/m2 plus PLD 30 mg/m2. The thirty patients treated in this study were heavily pretreated: 23 had received 1–5 prior chemotherapies (median 3), 15 received prior radiotherapy, and 27 had prior tumor related surgery. Grade 3 and 4 toxicities in pooled cycles were: ALT elevation (4%), neutropenia (3%), hand-foot syndrome (2%), AST elevation (1%) and nausea/vomiting (1%). One subject terminated treatment after 6 cycles due to adverse events. Six patients had a partial response and 14 patients have had stable disease for > 3 months. Images of the liver morphology from patients treated with this drug combination will be presented. Conclusions: Trabectedin and PLD can be combined at near full single agent therapeutic doses. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Johnson & Johnson Johnson & Johnson
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