Phase II, parallel-design study of preoperative combined modality therapy and the matrix metalloprotease (mmp) inhibitor prinomastat in patients with esophageal adenocarcinoma

Purpose: This randomized phase II, parallel-design study evaluated preoperative combined modality therapy and the matrix metalloprotease (MMP) inhibitor prinomastat in patients with resectable adenocarcinoma of the esophagus that were stage II or greater. The objectives of the trial were to determine pathologic complete response rate (pCR), overall response rate, progression-free survival, pattern of disease relapse, and two-year and overall survival. Patients and Methods: Preoperative staging included computed tomography, endoscopic ultrasound, and, when feasible, laparoscopy. Eligible patients were randomized to preoperative prinomastat or placebo, plus continuous infusion 5-FU, cisplatin, paclitaxel, and concurrent radiotherapy. Esophagectomy was performed on day 71. Adjuvant paclitaxel and prinomastat were available to all study patients. Results: Between August 2000 and June 2001, 15 of a planned 78 patients were randomized into the trial. One patient after randomization withdrew consent. Fourteen patients, 7 in each arm, completed preoperative treatment and surgery. pCR was achieved in 5 patients; 1/ 7 prinomastat and 4/ 7 placebo. Disease improvement was achieved in 7 patients; 5 /7 prinomastat and 2 /7 placebo. At a median follow-up of 28 months, 7 patients (2 prinomastat, 5 placebo) are alive with no evidence of disease. The primary prinomastat related toxicity was moderate to severe musculoskeletal toxicity interfering with daily function. This toxicity was managed with treatment rest, dose reduction, or discontinuation. Five patients (3 prinomastat and 2 placebo) had life-threatening thrombo-embolic events, which led to early evaluation of safety and efficacy, and subsequent termination of the study. Conclusions: All patients, regardless of treatment arm, were able to successfully undergo neoadjuvant combined modality therapy and esophagectomy. However, early closure of the study due to unexpected thrombo-embolic events precluded any conclusions regarding clinical activity of prinomastat in locally advanced esophageal cancer patients.