Phase I trial of imexon and docetaxel in patients with previously-treated stage IV non-small cell lung cancer, metastatic breast cancer or hormone-refractory prostate cancer. Free

LB-351

Background: Imexon (IMX) is an aziridine-containing small molecule that binds to thiols and induces pro-oxidative apoptotic effects in tumor cells. Combination drug studies in vitro showed that several classes of cytotoxic agents were synergistic with IMX, including the taxane-based agent, docetaxel. Methods: Phase I, dose-escalation trial (3 + 3 design) in patients with advanced, previously-treated solid tumors that are known to be sensitive to taxanes. Successive cohorts of patients were treated with escalating doses of IMX, IV over 30 minutes on days 1-5 with a single IV dose of docetaxel on day 1; Q3W, starting docetaxel at 75 mg/m², with de-escalation steps to 65 mg/m² and to 55 mg/m², if necessary for toxicity. Results: A total of 18 patients (non-small cell lung cancer (NSCLC: n = 6), metastatic breast cancer (n = 7), and hormone-refractory prostate cancer (n = 5) have been enrolled so far. Their median age was 56.5 years (range: 34 to 78) and 10 were men. The median number of prior therapies was 3.5 (range, 1 to 7). All were evaluable for toxicity. Seventeen patients were evaluable for response (lost to follow up, n = 1). The current dose level (level 5) includes 1300 mg/m² of IMX/75 mg/m² of docetaxel (n = 3 patients enrolled). The most common side effects were nausea/vomiting (during chemotherapy) and neutropenia. The only DLT occurred at dose level 3 (syncope) that did not recur in dose expansion of the cohort or at higher doses. There was one patient with prolonged stable disease (prostate cancer; 8 months) and three patients with objective responses: one PR (47% reduction by RECIST) (NSCLC) that lasted 5 months at which time the course was complicated by a concurrent primary renal cell cancer that required surgery; one 31% reduction (prostate cancer) that is too early to confirm on repeat restaging; one 26% tumor shrinkage (breast cancer who had had prior paclitaxel) and drop in CA27.29 from 1327 U/ml to 50.6 U/ml (normal range, 0-38 U/ml) (duration = 2 months). Conclusions: IMX can be combined safely at doses up to and including 1300 mg/m² with full-dose docetaxel with no initially observed increases in toxicities. Objective responses were seen in this trial, even in patients with several prior therapies including taxanes.