Assessment of trabectedin (T) induced liver toxicity with correlation to liver morphology in a phase I study of T + pegylated liposomal doxorubicin (PLD)

Abstract

9568 Background: T (ET-743) is a first-in-class compound that binds the minor groove of DNA. T has activity in soft tissue sarcoma and ovarian cancers with predictable, transient, non-cumulative and reversible hepatic toxicity, compatible with long term treatment. The combination of T and doxorubicin had preclinical synergistic activity. This study tested T + PLD in advanced malignancies. Methods: Eligibility included normal cardiac and liver functions, prior doxorubicin exposure <250 mg/m2. PLD 30 mg/m2 was administered iv 1-hour followed by 1 of 6 T doses (0.4 -1.3 mg/m2) iv 3 hours q 21 days. In select subjects (4 at pre/post cycle 1, 4 under long term treatment -cycle 14, 20, 30 and 30), liver biopsies were done with expert independent review. Results: Six dose levels of T were evaluated in 30 subjects. The DLTs were 1 grade 3 AST and 2 grade 4 ALT elevations seen at T 1.3 mg/m2. Grade 3–4 toxicities were: ALT elevation (4%), neutropenia (3%), hand-foot syndrome (2%), AST elevation (1%) and nausea/vomiting (1%). Liver biopsies were obtained from 8 subjects (1 in 0.6, 7 in 1.1 mg/m2 T dose cohorts), age 45–78 years, with sarcoma (4), and ovarian (2), uterine (1), and head and neck (1) cancers. T and PLD mean drug exposure for these subjects was 15 (2–36) and 12 (2–24) cycles, respectively. Mean total doses for T and PLD were 23.2 (3.4–39) and 597 (94–1296) mg, respectively. Findings included NASH (nonalcoholic steatohepatitis), severity ranging from minimal steatosis to moderate steatosis with fibrosis. Pre/post treatment biopsies showed no change in NASH pre/post in 3 cases, one subject had minimal post-treatment steatosis. No mitochondrial abnormalities or stellate cell activation were observed. Review concluded no evidence of persistent liver pathological abnormalities attributable to T. Conclusions: The MTD of T is 1.1 mg/m2 with 30 mg/m2 PLD q 21 days, and is well tolerated when both drugs are administered at near full therapeutic doses for prolonged periods. Liver biopsies did not demonstrate clinically relevant hepatic tissue toxicity. As reported previously, this is an active regimen which is being further evaluated in an ongoing Phase III study in relapsed ovarian cancer. [Table: see text]