Phase II study of three hour, weekly infusion of trabectedin (ET-743) in men with metastatic, androgen-independent prostate carcinoma (AIPC)

Abstract

4517 Background: Trabectedin (T) is a novel, marine-derived cytotoxic agent that binds to the minor groove of DNA and induces apoptosis and cell cycle arrest. T has been studied in phase I and II clinical trials in a variety of malignancies, and has clinical activity in soft tissue sarcoma, breast and ovarian carcinoma. Preclinical studies have demonstrated that low concentrations of T promote cell death in prostate cancer cell lines. Methods: We are conducting a phase II clinical trial to determine the efficacy and safety of T in men with AIPC. Men are treated with a weekly, three-hour infusion of T, at 0.580 mg/m2 for 3 out of 4 weeks. Inclusion criteria include adenocarcinoma of the prostate; androgen-independent disease by PSA criteria according to the PSA Working Group with testosterone<50 ng/ml; radiographic evidence of metastatic disease; and adequate hepatic function. Target accrual is 33 subjects. Results: A Simon’s two-stage design has been used, and based on the number of responses observed in the initial cohort, the trial has proceeded to the second stage. Twenty men have been enrolled to date, including 8 previously treated with docetaxel-based chemotherapy. Of those evaluable for response, there have been 3 men with a confirmed PSA response. One man with symptomatic, docetaxel-refractory AIPC has manifested an 86% decrease in PSA and rapid resolution of symptoms. Two other men have had PSA declines of 58.5% (first-line) and 79% (second-line following docetaxel/estramustine). Grade 3 adverse events related to study drug have been: elevated GGT (1 pt), thrombocytopenia (1 pt), fatigue (1 pt), and hyponatremia (1 pt). No grade 4 adverse events have been reported. Conclusions: Accrual should be completed in the next few months, and updated results will be presented. Preliminary results suggest that T is well tolerated and may have clinical activity in AIPC, including docetaxel-refractory AIPC. Additional studies including combination trials are warranted in this patient population. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration PharmaMar SA