Oxaliplatin plus raltitrexed in patients with advanced colorectal carcinoma - Results of a phase I-II trial

BACKGROUND. Oxaliplatin and raltitrexed both are active anticancer agents i n the treatment of patients with advanced colorectal carcinoma: They have d ifferent mechanisms of action and toxicity profiles and have shown at least additive effects in experimental and preliminary clinical studies. The aim of this disease oriented Phase I-II study was to determine the maximum tol erated dose (MTD), the dose-limiting toxicities (DLT), and the objective re sponse rate of this combination in patients with advanced colorectal carcin oma. METHODS. Between April 1998 and March 1999, 69 patients with measurable met astatic colorectal carcinoma who previously were unexposed to palliative ch emotherapy were enrolled. In the Phase I part of the study, 27 patients wer e treated with 3-weekly courses of a fixed dose of raltitrexed (3 mg/m(2) g iven as a 15-minute intravenous infusion) followed by a 2-hour infusion of oxaliplatin, which was escalated in consecutive cohorts of three to six pat ients from 85 mg/m(2) to 100 mg/m(2), 120 mg/m(2), 130 mg/m(2), and 140 mg/ m(2). After having defined the toxic dose, 42 additional patients were ente red at one dose level below to define the therapeutic index of this combina tion more precisely. RESULTS. In the Phase I part of the study, during the first three dose leve ls, only one patient each experienced DLT (Grade 3 increase in transaminase s, diarrhea, and stomatitis); at level 4, two of the first six patients ent ered had Grade 3 neutropenic infection or peripheral neurotoxicity, whereas dose level 5 (oxaliplatin 140 mg/m(2)) constituted the toxic dose with thr ee of three patients experiencing DLT (Grade 3 asthenia, transient amaurosi s, and diarrhea with Grade 4 neutropenia). Externally reviewed objective re sponses were noted in 9 of these 27 patients (33%), and stable disease occu rred in 12 patients (44.4%). Among the 42 patients who were treated subsequ ently at the MTD level (Phase II portion), 20 patients (47.6%) responded (9 5% confidence interval, 32-62.6%), and 21 patients (50%) had stable disease . Their median progression free survival was 9.0 months, and the median ove rall survival, with 42 patients (67%) currently alive, is > 14.5 months. Tr eatment tolerance at the MTD was acceptable, with only 9 of 42 patients (21 %) experiencing Grade 3-4 neutropenia; Grade 3 nonhematologic adverse react ions included increase in serum transaminases in 6 patients, peripheral neu ropathy in 3 patients, diarrhea in 3 patients, and both stomatitis and emes is in only 1 patient each. CONCLUSIONS, The described objective response and toxicity data, which are in agreement with preliminary results of other Phase I-II studies, support the promising therapeutic potential of this combination in the treatment of patients with advanced colorectal carcinoma. Due to its substantial antitu mor activity, tolerance (at the recommended MTD level), and convenient 3-we ekly outpatient administration schedule, further evaluation of this regimen seems warranted. (C) 2001 American Cancer Society.